Intradermal Therapy (Mesotherapy) with Lymdiaral in Chronic Venous Insufficiency and Associated Fibrosclerotic Edema Damage: A Pilot Study

Abstract

Objectives:

Chronic venous insufficiency (CVI) induces alterations that cause fibrosclerotic edema of the subcutaneous tissue. This study examined the effects of a complex naturopathic compound with vasoactive and antiedema activities (Lymdiaral®) administered intradermally.

Patients:

40 patients with signs and symptoms of CVI and associated fibrosclerotic edema of the subcutaneous tissue.

Outcome measures:

Efficacy was assessed by using clinical investigation, subjective and objective measures, and ultrasonography performed at baseline and after treatment.

Results:

Thirty-four patients completed the study; 6 of the original 40 (15%) had stopped for reasons unrelated to study treatment. The treatment was well tolerated. Fifteen adverse reactions were reported among a total of 378 doses administered (3.97%). None of these reactions were severe or required discontinuation of treatment. Subjective symptoms and objective measures improved, and ultrasonography showed statistically significant changes in hypodermal thickness of the medial aspect of the knees.

Conclusions:

Its open-label design and small sample size notwithstanding, this study indicates that intradermal therapy, according to the recommendation of the Italian Society of Mesotherapy, may provide a valuable contribution to the treatment of CVI and related fibrosclerotic edema of the subcutaneous tissue by prolonging the local effect of the pharmacologically active compounds. Comparative studies are needed to identify the broader clinical and economic benefits of local therapy compared with other systemic therapies.

Introduction

F ibrosclerotic edema of the subcutaneous tissue is a vascular disease resulting from damage to microvascular and connective tissue and capillary and venous stasis.^1
–3 In fact, it is described as a consequence of decreased blood flow in the microcirculation of the lower limbs, subsequent stasis, hypertension, increased capillary permeability, interstitial edema, and alteration of the interstitial matrix and vascular homeostasis.^4
–6 The interstitial edema results in the alteration of adipocyte cells, along with hypertrophy and hyperplasia of the reticular system, and of the micro-and macro-nodules of the sclerotic connective tissue.^1
–3 There is a correlation between the symptoms of venous stasis and fibrosclerotic edema of the subcutaneous tissue and symptoms of chronic venous insufficiency (CVI).^7
–9 The use of vasoactive drugs is indicated to treat structural changes, subjective symptoms (fatigue, night cramps, restless legs, heaviness, tension), and edema related to CVI.⁴

Phlebotrophic compounds appear to be the appropriate choice for patients with CVI who are unsuitable for or not indicated for surgery, or in whom surgery can be combined with pharmacologic therapy.^{4,10

–16}

Currently, however, systemic drug therapy for CVI only improves subjective symptoms and prevents complications; objective measures in patients receiving this therapy significantly improve less often. More recently, the role of the intradermal technique, commonly known as mesotherapy, has been better defined, including its role in the treatment of CVI.¹⁷ Mesotherapy is a minimally invasive technique used to administer small quantities of drugs or other bioactive substances through intradermal injections. It is used when other therapies have failed or when there is a possible synergistic benefit with other pharmacologic/nonpharmacologic therapies.

A previous study showed that drugs administered intradermally may exhibit local trophic action in patients with decubitus ulcers.¹⁸ In addition, both subjective and objective symptoms (venous pressure and calf circumference) improved in patients with CVI^19,20 and fibrosclerotic edema of the subcutaneous tissue.^21,22 The main goal of intradermal administration is to modulate the pharmacokinetic profile of the injected substance and to prolong the effects at a local level. In fact, one of the main advantages of mesotherapy is that a local pharmacologic effect can be obtained without the need for high systemic concentrations.¹⁷

The current study sought to evaluate the tolerability and efficacy of a naturopathic compound, comprising a set of active ingredients (Conium maculatum, 2.5 mg; Hydrastis canadensis, 2.5 mg; Phytolacca, 2.0 mg; Viscum album, 2.5 mg; Scilla, 2.0 mg) that interact with the interstitial matrix.^{23

–31} The compound was injected by the intradermal route, according to the Italian Society of Mesotherapy recommendations, in patients with CVI and related fibrosclerotic edema of the subcutaneous tissue.

Materials and Methods

Study protocol

This prospective, open-label study involved 40 female consecutively enrolled patients with CVI that resulted in fibrosclerotic edema of the subcutaneous tissue. Patients were excluded if they had edema associated with other diseases, incontinence of the saphenous-femoral valves, concomitant dietary therapy, or allergies; were pregnant or lactating; or had autoimmune diseases or cancer or were receiving therapies that could have interfered with the study protocol. After the ethics committee approved the study and patients provided written informed consent, patients were invited to receive a cycle of 10 sessions of mesotherapy (6 sessions of mesotherapy, 1 each week, followed by 4 sessions held once every 15 days). In each session, 4 mL of Lymdiaral® Injektopas (Pascoe-named, Lesmo (Milan) – Italy) was intradermally administered and distributed bilaterally in the trochanteric region, the medial aspect of the knee, and medial and posterior aspects of the leg, according to the recommendations of the Italian Society of Mesotherapy.¹⁷

Outcome measures

Tolerability was assessed at each visit, and efficacy was assessed at baseline and at 2 weeks after the end of treatment. Efficacy measures included an objective assessment, a subjective evaluation, and an ultrasonographic examination of the subcutaneous tissue at baseline and after treatment. Moreover, satisfaction was assessed at the end of the treatment cycle. The objective evaluation was performed by a blinded physician who had not participated in the study treatment. Objective evaluation included assessment of clinical signs of CVI (presence of telangiectasis, reticular veins, edema, varicose veins, cyanosis, and pain) using a scale of 1–4 points (1=none, 2=mild, 3=moderate, 4=severe). Subjective assessment (heaviness, swelling, pain, leg cramps, and feeling cold) was performed by using a numeric scale ranging from 0 (no symptom) to 10 (maximum of the intensity of symptom). Ultrasonography evaluated the subcutaneous tissue in the trochanteric region and medial aspect of the knee and ankle bilaterally^32
–34 with a 7.5-MHz linear probe (Pie Medical Ultrasound, Falco, Esaote, Genova, Italy). Ultrasonography evaluated the characteristics and development of the vascular connective branches, hypodermal thickness, and presence of edema in each region. Treatment satisfaction was assessed by using a visual analogue scale (VAS) consisting of a 10-cm line that corresponded to complete dissatisfaction on the extreme left and complete satisfaction on the extreme right.

Statistical analysis

Demographic and baseline characteristics and clinical data collected at each visit were summarized by using frequencies and percentage for dichotomous and categorical variables and mean±standard deviation, median, and minimum–maximum for continuous variables.

Changes between baseline (visit 1) and final visit for continuous variables were tested by using a t-test for repeated measures. Because some variables were not normally distributed, results were retested by using a nonparametric test (i.e., Wilcoxon signed-rank test) to confirm the results obtained with the parametric test. The Wilcoxon signed-rank test was also used to assess the changes of ordinal variables (e.g., clinical signs) between baseline and final visit. The statistical analysis was performed using SAS 9.2 for Windows (SAS Institute Inc., Cary, NC, USA).

Results

Forty patients were enrolled. The mean age was 34.6±8.45 years, and the mean body mass index was 22.2±2.95 kg/m². Of the 40 patients enrolled, 34 completed the treatment cycle of 10 sessions. Two patients withdrew from the study after eight sessions, one after seven sessions, one after six sessions, and two after five sessions. None of these patients left the study for reasons related to treatment. Moreover, during the study, 11 patients reported adverse reactions: five cases of tenderness (33%), three cases of hematoma (20%), three cases of burning (20%), two cases of pruritus (13.3%), one case of bruising (6.7%), and one case of a heaviness in the limbs treated (6.7%) in the injection of the substance administered. These reactions persisted from a few hours to as long as 3 days but did not require therapeutic intervention or discontinuation of treatment. Two patients temporarily discontinued the study for reasons unrelated to treatment, but they later finished the 10 sessions of treatment provided by the protocol (one patient had acute bronchitis and one had hives from insect bites). Another 15 patients reported concomitant disease that was not related to the study treatment and did not cause treatment interruption.

The subjective evaluation in 34 patients who completed the entire course of therapy showed that treatment was associated with a reduction in the intensity of symptoms (Table 1). The objectively evaluated results showed improvements in edema and pain in the cutaneous projection of the perforating veins (Table 2). Ultrasonography showed no significant changes in the trend of connective fibers between baseline and study end. In contrast, the hypodermal thickness of the medial aspect of the knee decreased (Table 3). Regarding hypoechogenicity, indicating the extent of edema, no significant change from baseline was evident after treatment (Table 4). However, in patients with severe edema at baseline, a trend toward a reduction of the degree of edema severity was observed after treatment. In fact, ultrasonography at baseline showed more severe hypoechogenicity than at the end of treatment (Table 5). The VAS analysis of satisfaction with treatment indicated a discrete treatment satisfaction score (mean, 6±2.4), and 50% of patients reported a VAS score of 7 or more.

Table 1.

Subjective Evaluation of Symptoms at Baseline and After Treatment in Patients Who Completed Treatment (n=34)

Symptom	Mean±SD	Minimum, maxium	Median	Difference from baseline	p-Value
Heaviness
Baseline	6.53±2.11	1.00, 10.00	7.00	2.0882	<0.0001
End of treatment	4.44±2.15	1.00, 8.00	5.00
Swelling	x	1.00, 1.00	x
Baseline	6.85±2.22	1.00, 10.00	7.00	2.0735	<0.0001
End of treatment	4.78±2.28	1.00, 10.00	7.00
Cramps		1.00, 1.00
Baseline	2.88±2.28	1.00, 8.00	2.00	1.0000	0.0207
End of treatment	1.88±1.53	1.00, 6.00	1.00
Cold		1.00, 1.00
Baseline	7.03±2.92	1.00, 10.00	7.50	3.2059	<0.0001
End of treatment	3.82±3.16	1.00, 10.00	2.50

Values were expressed according to visual analogic scale (from 0 to 10).

SD, standard deviation.

Table 2.

Objective Assessment of Clinical Signs at Baseline and at Final Visit in Patients Who Completed Treatment

Symptoms	Score	Patients at baseline, n (%)	Patients at final visit, n (%)	p-Value
Telangiectasis	Absent	10 (29.41)	10 (29.41)	p=0.1573
	Mild	16 (47.06)	18 (54.55)
	Moderate	8 (23.53)	5 (15.15)
	Severe	–	1 (2.50)
Varices	Absent	27 (79.41)	26 (78.79)	p=0.6547
	Mild	6 (17.65)	5 (15.15)
	Moderate	1 (2.94)	2 (6.06)
	Severe	–	–
Cyanosis	Absent	20 (58.82)	22 (66.67)	p=0.3020
	Mild	10 (29.41)	8 (24.24)
	Moderate	3 (8.82)	2 (6.06)
	Severe	1 (2.94)	1 (3.03)
Edema	Absent	1 (2.94)	4 (11.76)	<0.0001
	Mild	6 (17.65)	18 (52.94)
	Moderate	20 (58.82)	11 (32.35)
	Severe	7 (20.59)	1 (2.94)
Pain	Absent	3 (8.82)	12 (35.29)	<0.0001
	Mild	7 (20.59)	16 (47.06)
	Moderate	16 (47.06)	6 (17.65)
	Severe	8 (23.53)	–
Total		34 (100)	34 (100)

Table 3.

Detailing Thickness of Hypoderma on Ultrasonography at Baseline and Final Visit of Patients Who Completed Treatment (n=34)

Site	Mean±SD	Minimum, maxium	Difference from baseline	p-Value
Trochanteric apex, right
Baseline	2.46±0.75	1.40, 4.30	−0.0368	0.5984
End of treatment	2.42±0.83	1.47, 4.86
2 cm below trochanteric apex, right
Baseline	2.89±0.80	1.64, 4.89	−0.00353	0.9652
End of treatment	2.89±0.83	1.83, 5.24
Trochanteric apex, left	=
Baseline	2.40±0.67	1.52, 4.84	0.0318	0.6199
End of treatment	2.43±0.73	1.48, 4.70
2 cm below trochanteric apex, left
Baseline	2.83±0.71	1.87, 5.38	0.0659	0.3862
End of treatment	2.90±0.72	1.91, 5.13
Inner region of knee, right
Baseline	1.22±0.35	0.50, 1.93	−0.2035	0.0002
End of treatment	1.01±0.35	0.46, 2.28
Inner region of knee, left
Baseline	1.31±0.33	0.60, 2.30	−0.1935	0.0003
End of treatment	1.11±0.40	0.38, 2.22
Inner premalleolar region, right
Baseline	1.10±0.29	0.40, 1.85	0.0268	0.5185
End of treatment	1.13±0.29	0.56, 0.56
Inner premalleolar region, left
Baseline	1.21±0.34	0.53, 1.95	−0.0376	0.4487
End of treatment	1.18±0.37	0.54, 2.15

Values are expressed in centimeters (cm).

SD, standard deviation.

Table 4.

Ultrasonographic Results Showing Variations of Hypoechogenicity of Cellular Tissue at Baseline and After Treatment in Patients Who Completed Treatment (n=34)

Site	Hypoechogenicity	Left site	Right site
Trochanteric region	Increased	5 (14.71)	5 (14.71)
	Unchanged	21 (61.76)	20 (58.82)
	Reduced	8 (23.53)	9 (26.47)
Inner region of knee	Increased	3 (8.82)	2 (5.88)
	Unchanged	25 (73.53)	21 (70.59)
	Reduced	8 (17.65)	8 (23.53)
Inner premalleolar region	Increased	2 (5.88)	1 (2.94)
	Unchanged	25 (73.53)	26 (76.47)
	Reduced	7 (20.59)	7 (20.59)
Total		34 (100)	34 (100)

Hypoechogenicity of different sites is described as increased, unchanged, or reduced versus basal time. Numbers show patients who completed the treatment (%).

Table 5.

Ultrasonographic Results Showing Hypoechogenicity of Cellular Tissue at Baseline and After Treatment in Patients Who Completed Treatment (n=34)

		Left site		Right site
Site	Hypoechogenicity	Baseline	End of treatment	Baseline	End of treatment
Trochanteric region	Moderate	16 (47.06)	19 (55.88)	16 (47.06)	20 (58.82)
	Severe	18 (52.94)	15 (44.12)	18 (52.94)	14 (41.18)
Inner region of knee	Moderate	9 (26.47)	12 (35.29)	9 (26.47)	15 (44.12)
	Severe	25 (73.53)	22 (64.71)	25 (73.53)	19 (55.88)
Inner premalleolar region	Moderate	4 (11.76)	9 (26.47)	4 (11.76)	10 (29.41)
	Severe	30 (88.24)	25 (73.53)	30 (88.24)	24 (70.59)
Total		34 (100)	34 (100)	34 (100)	34 (100)

Hypoechogenicity of different sites is described as increased, unchanged, or reduced versus basal time. Numbers show patients who completed the treatment (%).

Discussion

CVI is a clinical condition with significant social and economic implications.⁴ Recent data also suggest that 53% of patients older than 50 years of age have objective symptoms, such as venous reflux, varicosities, and telangiectases, and subjective symptoms, such as heavy (79%) and tired (78%); these symptoms are common in women without correlation to age.³⁵ Moreover, the clinical signs of subcutaneous tissue disorder caused by edema and fibrosclerosis constitute so-called cellulite,^1
–3 which is a cosmetic condition and a common concern of many patients.

The current study showed that the treatment, consisting of 10 sessions with intradermal administration of a complex naturopathic compound (Lymdiaral®), was well tolerated. A total of 15 adverse reactions were reported among 378 doses of the drug administered (3.97%). These adverse reactions were compatible with the type of drug and the micro-trauma induced by the needle. Moreover, treatment was associated with an improvement in subjective symptoms and objective signs. Furthermore, ultrasonography showed an improvement in the thickness of the hypodermis in the medial aspect of the knee. This study, despite its open-label design and the limited number of patients, confirms the tolerability and efficacy of an intradermally administered vasoactive compound in the treatment of CVI and related fibrosclerotic edema of the subcutaneous tissue. These findings need to be confirmed in large randomized clinical trials.

Conclusions

Intradermal therapy with a cycle of treatment, as recommended by the Italian Society of Mesotherapy,^{17, 36} performed with a complex naturopathic compound (Lymdiaral®) in patients with CVI and associated fibrosclerotic edema of the subcutaneous tissue is well tolerated and effective in reducing objective and subjective symptoms.

Footnotes

Acknowledgments

The authors thank Sergio Maggiori, Fulvio Tomaselli, and Carlo Alberto Bartoletti for having stimulated clinical research in the field of the aesthetic medicine. Content Ed Net helped prepare the manuscript. This study was funded by Named.

Physicians and biostatistitian panel: Acinapura RA, Caputo MG, Carota A, Centofanti D, Cuguttu A, Denni A, Di Maggio R, Dorato D, Feleppa D, M. Fontevecchia M, Fraone N, Giardini M, C. Guglielmo C, Jacovitti S, Loffredo F, Marchionne A, Montanaro F, Nazzaro L, Pompilio A, Salciccia PL, Santini S, Trocchi G, Troili F, Veraldi M, Zannella C.

Disclosure Statement

The authors declare no conflicts of interest related to the contents of this article. Dr. Enrica Maggiori is the guarantor for this article and takes responsibility for the integrity of the work as a whole.

References

Merlen

, Curri

, Sarteel

. Cellulitis, a conjunctive microvascular disease. Phlebologie, 1979; 32:279–282.

Merlen

. The role of cellulitis in vascular pains. Angeiologie, 1966; 18:21–24.

Merlen

. Physiopathology of sclerous cellulitis. Phlebologie, 1981; 34:537–541.

Agus

, Allegra

, Antignani

et al. Guidelines for the diagnosis and therapy of the vein and lymphatic disorders. Int Angiol, 2005; 24:107–168.

Pratesi

. Microcircolazione e microangiologia. Fisiopatologia, Clinica e Terapia. Torino, Italy: Minerva Medica, 1990; 488.

Bilancini

, Lucchi

, Tucci

et al.

Leukocyte entrapment in chronic venous stasis: myth or reality?

Phlebologie, 1992; 45:513–518.

Curri

. Adiposità localizzata e pannicolopatia edematofibrosclerotica. Milano, Italy: Sepem Ed, 1990; 12–117.

Curri

. Compendio di semeiotica clinica e strumentale della pannicolopatia. Milano, Italy: Edra Ed, 1993; 1–160.

Curri

. Liposclerosi e microcircolo. Dermoestetica, 1990; 1:6–7.

10.

Allegra

, Bartolo

Jr , Carioti

, Cassiani

. An original microhaemorheological approach to the pharmacological effects of Daflon 500 mg in severe chronic venous insufficiency. Int J Microcirc Clin Exp, 1995; 15,Suppl 1:50–54.

11.

Coleridge Smith

. Pharmacological treatment for venous disease. Phlebology, 1994; 9:47.

12.

Lyseng-Williamson

, Perry

. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs, 2003; 63:71–100.

13.

Merlen

J.F.

Rutines et troxerutine: microcirculation et hémorhéologies. London: John Libbey Eurotext, 1985; 102.

14.

Nicolaides

. Venous disease and phlebotherapy. Phlebology, 1992; 7 Suppl 2:1–3.

15.

Ramelet

. Clinical benefits of Daflon 500 mg in the most severe stages of chronic venous insufficiency. Angiology, 2001; 52,Suppl 1:S49–56.

16.

Zaragoza-Garcia

, Domiugues-Rodrigues

. Mechanism of action of the venotonic drugs. Scope Phlebol Lymphol, 1998; 5:16–19.

17.

Mammucari

, Gatti

, Maggiori

et al. Mesotherapy, definition, rationale and clinical role: a consensus report from the Italian Society of Mesotherapy. Eur Rev Med Pharmacol Sci, 2011; 15:682–694.

18.

Pezone

, Martini

, Iacono

. Mesotherapy in the treatment of deb-sores in spinal patients. Mesotherapy, 1981; 1:67–69.

19.

Gallo

. Mesotherapy in phlebology. Phlebologie, 1980; 33:153–156.

20.

Tomaselli

, Scondotto

, Sforza

. First data on the use of mesotherapy controlled in the treatment of phlebolymphedemas. J Mesother, 1981; 1:71–76.

21.

Bartoletti

, Gualtierotti

, Tomaselli

. Mesotherapy and gel frigotherapy in the treatment of “cellulitis” and phlebolymphoedemas in the lower limbs. J Mesother, 1981; 1:127–138.

22.

Maggiori

, Bartoletti

, Maggiori

et al. Local intradermotherapy (ITD) with mesoglicano in PEFS and IVLC: retrospective study. Trends Med, 2010; 10:73–78.

23.

Albergati

, Bacci

. Valutazione degli effetti microcircolatori di Lymdiaral in pazienti affetti da flebolinfedema: studio clinico in doppio cieco, randomizzato e controllato con placebo. Medicina Funzionale, 2000; 3:3–13.

24.

Albergati

, Bacci

. Valutazione degli effetti microcircolatori di Lymdiaral a dosaggi incrementali in pazienti affette da flebolinfedema: studio clinico in cross-over, randomizzato, in doppio cieco e controllato con placebo. Medicina Funzionale, 2000; Suppl 4:1–8.

25.

Albergati

, Bacci

. Valutazione dell'attività di Lymdiaral sulla omeostasi endoteliale nella stasi circolatoria: studio clinico pilota in doppio cieco, randomizzato, controllato con placebo ed in cross-over. Linfologia Italiana, 2004; 1:27–33.

26.

Campisi

, Zilli

, Eretta

et al. Efficacia di Lymdiaral nel trattamento del linfedema cronico degli arti: studio caso controllo. Linfologia Italiana, 2004; 1:13–14.

27.

Gasbarro

, Castaldi

, Poverini

, Medini

, Colombani

, Gresta

. Trattamento topico e mesoterapico con Lymdiaral in pazienti affette da PEFS. Medicina Funzionale, 2004; 3:1–4.

28.

Heydecker

, Albergati

. Valutazione dell'attività di Lymdiaral in associazione con terapia intradermica nell'adiposità localizzata trocanterica: studio randomizzato confrontato con placebo. Medicina Funzionale, 2007; 2:8–16.

29.

Heydecker

, Albergati

. Valutazione dell'attività di Basentabs nella PEFS agli stadi intermedi in associazione a Lymdiaral e Veno. Medicina Funzionale, 2007; 2:2–7.

30.

Heydecker

, Albergati

. Studio randomizzato verso placebo di Lymdiaral in ambiente alcalino indotto alcalino indotto daBasentabs in associazione con lipodissoluzione iniettiva nell'adiposità localizzata trocanterica. Medicina Funzionale, 2008; 1:2–9.

31.

Liguori

, Sarcinella

. Valutazione degli effetti della terapia con Lymdiaral nei linfedemi degli arti superiori mediante studio dell'emodinamica microcircolatoria con metodica laser doppler. Medicina Funzionale, 2004; 1–4.

32.

Giannini

, Ceccarelli

, Bartoletti

. Aspetti ecografici del tessuto adiposo sottocutaneo normale nelle aree di studio della PEFS. La Medicina estetica, 1992; 16:1–5.

33.

Giannini

, Ceccarelli

, Valeriani

, Bartoletti

. La metodica ecografica come screening nello studio della pannicolopatia edemato-fibrosclerotica. Quadri di semeiotica ecografica. La Medicina Estetica, 1994; 17:267–270.

34.

Giannini

, Ceccarelli

, Valeriani

, Bartoletti

. Quadri ecografici ed aspetti anatomo-patologici della pannicolopatia edemato-fibrosclerotica. La Medicina Estetica, 1994; 18:123–126.

35.

Chiesa

, Marone

, Limoni

et al. Chronic venous insufficiency in Italy: the 24-cities cohort study. Eur J Vasc Endovasc Surg, 2005; 30:422–429.

36.

Mammucari

, Gatti

, Maggiori

, Sabato

. Role of mesotherapy in musculoskeletal pain: opinions from the italian society of mesotherapy. Evid Based Complement Alternat Med, 2012; 2012:436959.