Mesotherapy andInjection Lipolysis

Alan Matarasso, MD, FACSa,b,c,d,*,Tracy M. Pfeifer, MD, FACSb,c,e

KEYWORDS� Mesotherapy � Subcutaneous fat reduction� Injection lipolysis � Phosphatidylcholine� Sodium deoxycholate

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Plastic surgeons continue to seek refinement,improvements, and safety in existing techniques,and patients often seek less-invasive procedures,improved results and solutions for complexproblems.

These are some of the reasons that mesother-apy and injection lipolysis have experiencedsome popularity in the United States. Althoughsome studies are emerging in the English medicalliterature to document the safety and efficacy ofinjection lipolysis, in the United States the enthu-siasm among patients and physicians largely hasbeen driven by reports in the lay press and thequest for permanent fat reduction by nonsurgicalmethods. Because of this and for other reasons,controversy has surrounded mesotherapy andinjection lipolysis. The primary concern is that theclinical application of these methods in patientshas preceded rigorous scientific study of theseagents and their application that would be neces-sary to establish safety and efficacy required forUS Food and Drug Administration (FDA) approval.

The purpose of the first part of this article is tofamiliarize the reader with the evolution of meso-therapy, injection lipolysis, and the use ofphosphatidylcholine and deoxycholate for subcu-taneous fat reduction. There is an emphasis onthe underlying basic science of fat metabolismand the biochemistry of phosphatidylcholine, sothat practitioners will be able to understand futurepublished research on these topics. The secondhalf of the article details some personal experiencewith injection lipolysis.

a Department of Plastic and Reconstructive Surgery, Albb Department of Plastic Surgery, Manhattan Eye, Ear anc Division of Plastic Surgery, Lenox Hill Hospital, New Yod Private Practice, 1009 Park Avenue, New York, NY 100e Private Practice, 565 Park Avenue, New York, NY 10028* Corresponding author.E-mail address: matarasso@aol.com (A. Matarasso).

Clin Plastic Surg 36 (2009) 181–192doi:10.1016/j.cps.2008.11.0020094-1298/08/$ – see front matter ª 2009 Published by E

MESOTHERAPY

Recently, there has been a renewed interest in thetechnique of mesotherapy as a method ofreducing subcutaneous fat for body contouring.Most sources credit Pistor with having developedthe technique of mesotherapy in France in 1952.1

Practitioners of mesotherapy in France, however,can trace the roots of mesotherapy to 2000 BC inChina (T Pfeifer and DI Duncan, personal commu-nication, 2008). Others place the time even earlierat 3000 BC. The modern era of mesotherapy,however, began in approximately 1952, when Pis-tor injected a partially deaf patient with intravenousprocaine for the treatment of an acute asthmaattack.2 This was a standard treatment for asthmaat the time. Surprisingly, the patient experiencedimproved hearing for several hours. Noting thetemporarily improved hearing after intravenousprocaine injection, Pistor began injected procaineinto the superficial dermis in close proximity tothe ear. Surprisingly, in some patients a reductionin cervical pain was noted. According to Petit,a mesotherapy practitioner in France, Pistor wasmarginalized and seen as a healer rather than asa physician. Pistor subsequently coined the termmesotherapy to describe treatment of the meso-derm. He believed that the local injections hadan effect on tissues originating from the meso-derm, one of the three primary germ layers of theembryo, which develops into the dermis of theskin, connective tissue, muscle, and the circula-tory system. At its inception, mesotherapy referred

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specifically to intradermal injections, and mostpublications still define mesotherapy as intracuta-neous injections. Mesotherapy, however, hasevolved to include injections into the epidermisand dermis, subcutaneous injections and regionalinjections. The French Society of Mesotherapywas founded in 1964, and the applications of mes-otherapy soon expanded. In 1980, the Cerclesd’Etude et de Recherche en Mesotherapie(CERM) was formed. The CERM is a researchgroup formed to study mesotherapy. In 1982, Pis-tor created the International Society of Mesother-apy. In 1987, mesotherapy was recognized bythe French Academy of Medicine as a medicalspecialty. Also in 1987, the first advanced degreein mesotherapy was established in Marseille, andin 1996, Petit organized a degree program inBordeaux. Over the years, mesotherapy hasgained acceptance in many countries, and inFrance, both physicians and patients recognize itas an integral part of health care.

The goal of mesotherapy injections is to stimu-late the mesoderm for various biological purposes.The substances injected include: vasodilators,anti-inflammatory medication, muscle relaxants,proteolytic enzymes, vitamins, minerals, plantextracts, vaccines, antibiotics, hormones,hormone blockers, and anesthetics.3 Recently,phosphatidylcholine and deoxycholate have beenused in subcutaneous injections. Most mesother-apy formulas contain a vasodilator. The reasonfor this is not entirely clear, but recent work byDuncan has shown that the vasodilator results ina more rapid clearing or uptake of injected phos-phatidylcholine and deoxycholate (TM Pfeifer,and DI Duncan, personal communication, 2008).Thus, the vasodilator may be useful for patientswho have conditions requiring vasodilation fortreatment or those in whom systemic uptakeof the injected medication is desirable. Generally,the formula or cocktail injected is determined bythe practitioner, according to the needs of theparticular patient. Thus, standardized formulasfor the most part do not exist. The lack of standardingredients and formulas further contributes to theinability to extrapolate data and compare results.Mesotherapy has been advocated for treating anassortment of conditions as varied as chronicpain, vascular disease, psoriasis, and rheumatoidarthritis. In France, mesotherapy primarily is usedto treat nonaesthetic conditions including sportsinjuries and chronic pain; its use for aestheticpurposes is limited. In the United States, practi-tioners primarily have used mesotherapy foraesthetic purposes including: the treatment ofcellulite, weight loss, spot weight loss, skin rejuve-nation, hair loss, and the treatment of facial

rhytids. The theory is that mesotherapy helpsreverse the physiology of the condition. Thecompounds injected are usually a combination ofdifferent ingredients and are chosen based onthe pathophysiology of the disease. For example,rheumatoid arthritis is treated using anti-inflamma-tory medications and plant agents thought tocontrol inflammation.

In the United States, the first reports of meso-therapy appeared in the lay press in December2001.4 In January 2003, People magazine reportedthat the singer Roberta Flack lost 30 pounds ona weight loss program that included mesotherapyadministered by a physician who studied meso-therapy in Paris; the story also reported that mes-otherapy treatments to the face resulted in ‘‘ayouthful glow.’’5 After these initial reports, meso-therapy received a significant amount of presscoverage in the United States. Patients began re-questing mesotherapy and very little, if any, scien-tific information written in English was available toAmerican physicians. At the time, most of the pub-lished medical literature was in French. JacqueLe Coz, former president of the French Society ofMesotherapy, has written extensively on thesubject of mesotherapy.6 Although all of his booksare written in French, in 2008 he translated hismost recent book into English.7 Recently, Mad-here of New York edited a textbook on mesother-apy published in English. The book provides anoverview on the topic and specific information onmesotherapy not readily available to Americanphysicians.8 The book includes chapters writtenby widely respected French practitioners of meso-therapy and American leaders in the field ofmesotherapy.

Multiple injection techniques exist for mesother-apy, and there is debate within the community ofmesotherapy practitioners as to which techniquesare most appropriate. Injections can be:

Intraepidermic (IED)Papule (IDS), in which a bleb is raised at the

junction of epidermis with the dermisNappage, in which two to four injections are

made per second, spaced 2 to 4 mm apartat an angle of 30� to 60�

Point-by-point (PPP) injections are placed inthe dermis at approximately 4 mm depth

Specific systemic mesotherapy injections areplaced in the deep dermis and hypodermisfor treating rheumatologic disorders andpain management

Mesoperfusion injections involve the slowinjection over 30 to 90 minutes of 2.5 to10 cc, placed 4 to 13 mm deep, for treatinginsomnia and chronic pain

Mesotherapy and Injection Lipolysis 183

Subcutaneous injections, which are beingused in the treatment of subcutaneousfat, as in injection lipolysis

Mesotherapy can involve 8 to 300 injections pertreatment; treatments are weekly or every otherweek. The number of treatments varies and rangesbetween 3 and 15 injection sessions, dependingon the condition. Injections are administered eitherby a standard syringe, usually either 5 or 10 cc, orusing a hand-held device, called a mesogun,which has a syringe and needle (27 or 30g)attached; the volume of injection can be varied.Injection needles are typically 4 mm long. Thevolume of injection is usually very small. Mesogunsmay be either automatic or semiautomatic, andthey can be purchased for approximately $2000to $8000.9 Fully automatic mesoguns advancethe needle and deliver the injection. Semiauto-matic mesoguns require manual advancement ofthe needle or trigger-operated delivery of the injec-tion. One mesogun is approved by the FDA, theDermotherap by USA Meso.

In the United States, the clinical application ofmesotherapy in patients is controversial for severalreasons. The primary criticism of mesotherapy isthat it is unproven from a scientific standpoint.The lack of standardized formulas and protocolsmakes it virtually impossible to validate resultsand reports of efficacy by replication of studies.Widely practiced in Europe and South America,the bulk of specific reports on mesotherapy arepublished in French, Italian, and Spanish litera-ture.10–18 There is a paucity of rigorous scientificstudies published in the English medical literatureregarding the safety and efficacy of mesother-apy.19 The overall safety of mesotherapy is notwell-documented. There are reports in the litera-ture, however, of complications and side effectsincluding ulceration, prolonged swelling, pain,panniculitis, skin ulceration, abscess, hematoma,psoriasis, atypical mycobacterial infections, urti-caria, and hyperpigmentation.20–31

A second criticism is that although some of theindividual ingredients injected during mesotherapyare known, these substances usually are used incombination. The individual practitioner oftendetermines the particular combination of ingredi-ents used for a given treatment. There is concernabout unknown interactions between the medica-tions combined in each cocktail. Furthermore, the‘Tratado de Mesotherapia’ is a handbook only pub-lished in Spanish, describing the various applica-tions of mesotherapy, active agents used, andrecommended protocols; it includes an extensivebibliography.32 It is available through LaboratoriesMesoestetic Limited, a company based in Spain

that also manufactures and sells the productsused mesotherapy.33 At this time, an English trans-lation is not available. One publication in the Englishmedical literature describes the practitioner’sprotocols for reduction of subcutaneous fat, treat-ment of cellulite, mesoglow (skin rejuvenation),and mesohair (treatment of hair loss).19 Althoughthe exact formulas used are given, a precisedescription of injection protocol is not provided.

As in any other aspect of medicine, physiciansinterested in practicing mesotherapy need trainingin its methods. This includes knowing the exactmedications used, understanding the pharma-cology of medications used in mesotherapy, tech-nical training on appropriate delivery methods, andunderstanding the possible complications andcontraindications of the procedure. In someinstances, physicians can access this informationonly through courses for which there is a fee tothe physician participant. This commercializationof the sharing of scientific information that maybenefit patients is somewhat in contradictionwith the tenets of medicine. This proprietaryapproach conflicts with the time-honored traditionof an altruistic free and open exchange of scientificinformation in the interest of providing care andtreatment for patients.34

Additional controversy arises from the fact thatin some countries, including the United States,practitioners of mesotherapy include both properlytrained medical personnel and unlicensed practi-tioners. Brazil banned the use of Lipostabil in mes-otherapy in part because of its use by unlicensedpractitioners and resulting complications.35 In theUnited States, many medispas offer mesotherapyadministered by unsupervised nurses or aestheti-cians to their clients without having a physicianevaluate and treat the patient. In addition, othernonphysician professionals such as chiropractors,dentists, and massage therapists are starting tooffer mesotherapy. Nonsurgeon physicians maytake a course to learn about mesotherapy. Thisleads to practitioners of mesotherapy who arenot fully trained in the technique. Additionally,these practitioners do not have the ability to fullyevaluate the patient’s condition and offer appro-priate alternative treatments. Moreover, they maynot be able to diagnose and treat a complication.Some states require a physician be on site andhave evaluated the patient before treatment;others do not. Even in states requiring on-sitesupervision and evaluation by physicians, medi-spas staffed only by nurses or aestheticianscontinue to offer mesotherapy to their clients.

The practice of mesotherapy by unlicensedpersonnel has had several unfortunate conse-quences. First, when complications occur, it is

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often when mesotherapy is performed bynonmedical personnel. Second, with medispasand salons offering mesotherapy, the public falselyassumes that mesotherapy is a procedure akin toother beauty treatments such as, for example,waxing. Patients assume mesotherapy is not thepractice of medicine and therefore harmless.What should be considered a medical treatmentthus is trivialized, and the entire technique andtreatment modality is harmed. Patients areunaware of the potential complications of meso-therapy, can be victims of unscrupulous practi-tioners of mesotherapy, and may fall prey toaggressive marketing practices by businessescommercializing mesotherapy for profit. Third,patients know that the practice of medicine isregulated by the state and federal government.Therefore, patients believe that if mesotherapy isa medical treatment and being administered bynonmedical personnel, that the treatment mustbe safe, because the government allows this prac-tice. Most physicians probably would agree thatprocedures that can result in deformity and othersignificant complications should be consideredthe practice of medicine. What constitutes thepractice of medicine, however, is defined by statelaw, which varies from state to state. Some statesconsider a procedure that results in penetration ofthe skin to be the practice of medicine. Otherstates apparently do not consider mesotherapyto be the practice of medicine. Even in states inwhich mesotherapy meets the definition of thepractice of medicine, enforcement of state lawsand statues may be difficult.

The aforementioned issues, including the lack ofscientific information, unregulated practice andfailure to share information in the usual scientifictradition has led to serious doubt and skepticismabout mesotherapy and the appropriateness ofphysicians offering these nonproven treatmentsto their patients.

Mesotherapy injection ingredients are inexpen-sive and easy to acquire. For example, aminoph-ylline 25 mg/mL, 20 cc vial can be purchased forapproximately $2.25 per vial.36 Although themedications used in mesotherapy may be FDA-approved for other indications, no medication isapproved by the FDA for use in mesotherapy. Itis important to clarify that the FDA does notconsider the use of FDA-approved drugs in mes-otherapy to be an off-label use. The FDA hasthree categories for drugs and devices used inpeople:

1. Approved for a specific use (labeled andapproved by the FDA for marketing)

2. Approved and permitted for off-label use

3. Nonapproved (not approved by the FDA for anypurpose and ineligible for off-label use)

With a few exceptions such as collagenase,hyaluronidase, local anesthetics, and calcitonin,the medications used in mesotherapy are notapproved by the FDA for intradermal or subcuta-neous injection.37 FDA drug approval includesthe delivery method. Thus, if one injects a medica-tion intradermally that is FDA approved for intrave-nous administration, this does not constituteoff-label usage. This would be a nonapproveduse. Off-label usage refers to the use of an FDA-approved drug, including method of administra-tion, for an indication other than for which it wasapproved.

MESOTHERAPY FOR SUBCUTANEOUSFAT REDUCTION

Mesotherapy has been used for several years inEurope and South America for body contouringand has been advocated as a nonsurgical alterna-tive to liposuction.

Mesotherapy for fat reduction often is used inconjunction with dietary modification, hormonereplacement therapy, exercise, and nutritionalsupplements. Thus, it can be difficult to preciselyidentify the contribution of mesotherapy to anyreduction in subcutaneous fat, if there is one.

Park recently examined the results of mesother-apy in 20 women enrolled in a prospective, case-controlled study.38 The study was designed toevaluate the effectiveness of mesotherapy usingaminophylline, buflomedil (non-FDA approvedvasodilator) and lidocaine to reduce subcutaneousfat in the medial thigh. The change in fat was eval-uated by measuring circumference and by CTscanning. The authors found there was no differ-ence in circumference or any difference in cross-sectional area or thickness of the fat layer byCT scan. In contrast, other practitioners reporta reduction in subcutaneous fat after mesother-apy. In 1995, Greenway reported a reduction inthigh girth in women injected with isoproterenol.39

Patients in this study and in a second study byGreenway, who applied topical creams containingaminophylline and other substances, also experi-enced a reduction in thigh girth.40

In 2004, two plastic surgeons presented anabstract evaluating the use of mesotherapy forbody contouring and cellulite treatment.41 Fortypatients were enrolled in a double-blinded,prospective study; a single body region wastreated by mesotherapy on a weekly basis for5 weeks, followed by monthly maintenancetherapy. The patients were separated into four

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groups. Group 1 (N510) received mesotherapytreatments unilaterally; group 2 (N510) receivedtreatments bilaterally. Group 3 (N510) receivedmesotherapy in association with dietary modifica-tion and exercise, and group 4 (N510) receivedsaline placebo injections. Patients were surveyedby questionnaire and evaluated by a physicianwho was blinded. Objective evaluation includedmeasurement of circumference and pinch test.Most patients treated with mesotherapy reporteda noticeable difference in the treated area (groups1 and 3, 18 out of 20; group 2, 7 out of 10). Circum-ference measurements decreased in mostpatients who were treated. The average decreasein circumference was 2.6 cm at the waist and1.8 cm at the thigh; the greatest circumferencedecrease was 3.8 cm at the waist and 2.5 cm atthe thigh. In all treated groups, the appearanceof cellulite was reduced dramatically. No majorcomplications occurred; several minor complica-tions were observed. These included transienterythema of the treated area in six patients, onelocalized infection at an injection site, minimalecchymosis in five patients, and significant ecchy-mosis in one patient.

Research is starting to clarify the mechanismsby which mesotherapy for reduction of subcuta-neous fat and cellulite reduction possibly couldwork. It is known that lipolysis of fat stored inadipocytes is regulated by alpha-2 and beta-adre-noreceptors on the adipocyte cell surface. Beta-receptor activity increases lipolysis, and alpha-2receptor activity inhibits beta-receptors.

A theoretic possibility is that compounds thatpromote beta-activation and alpha-2 inhibitionmay increase rates of lipolysis. In the case of mes-otherapy for reduction in subcutaneous fat andcellulite reduction, the theory is that stimulationof the adipocyte beta-adrenergic receptor causesa resultant increase in lipolysis. Isoproterenol, oneof the agents commonly used in mesotherapy, isa beta-receptor stimulator. In addition to beta-receptor stimulators, other substances includingestrogen and thyroid as well as methylxanthinescaffeine and aminophylline are known to increaselipolysis.42,43 Several publications describeenhanced lipolysis in adipose tissue perfusedwith isoproterenol.44,45 In 2007, Caruso reportedthat isoproterenol, aminophylline, yohimbine, andMelilotus stimulate lipolysis as evaluated by an invitro assay.46 Others, however, believe that theincreased lipolysis seen after beta-receptor stimu-lation by mesotherapy injections is fundamentallydifferent from that seen after injection lipolysiswith phosphatidylcholine and deoxycholate (DIDuncan and P Rubin, personal communication.When beta-receptor stimulators such as

epinephrine are injected, a transient increase isseen in blood triglyceride levels. This might corre-spond to a temporary decrease in adipocytetriglyceride levels. After the effects of beta-receptor stimulation have worn off, the triglycer-ides are restored in the adipocyte. Under thishypothesis, one can presume no permanentchange in the adipocyte volume. The theory postu-lates that cell wall disruption and subsequentnecrosis of the adipocyte must occur for a perma-nent reduction in subcutaneous fat to occur. Withrespect to cellulite, enhanced lipolysis also hasbeen postulated as the mechanism by which cellu-lite is improved after mesotherapy. One recentstudy using microdialysis assays, however,showed no difference in rates of lipolysis betweencellulite and noncellulite adipose tissue.47 Otherproposed mechanisms for how mesotherapyresults in spot fat reduction include enhancedcirculation and alterations in connective tissue.

INJECTION LIPOLYSISWITHPHOSPHATIDYLCHOLINE

As discussed previously, mesotherapy has beenapplied to the reduction of subcutaneous fat.Recently, there has been interest in injection lipol-ysis, the subcutaneous injection of phosphatidyl-choline and deoxycholate for subcutaneous fatreduction.

Phosphatidylcholine is a naturally occurringglycerolphospholipid composed of glycerol withtwo fatty acids and choline attached. It has threeimportant functions:

1. It emulsifies dietary fat, thereby playing a vitalrole in digesting dietary fat.

2. It is a component of the apolipoproteins essen-tial to cholesterol metabolism.

3. It is an essential component of cellmembranes.48

Phosphatidylcholine contributes to the propermetabolism of fat and cell membrane integrity, isimportant in neuron conduction, increases thesolubility of cholesterol, is the precursor to acetyl-choline, and is a surfactant in the alveoli of thelungs. Phosphatidylcholine is able to emulsifyblood fats, resulting in increased surface area ofchylomicrons, allowing quicker breakdown oftriglycerides by the enzyme lipoproteinlipase.

Phosphatidylcholine is consumed in a normaldiet and is also available as oral supplements.Oral phosphatidylcholine is considered a dietarysupplement and therefore is not regulated by theFDA. Oral phosphatidylcholine supplements areused to guard against low blood choline levels

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and to restore blood choline levels in patientssuffering from select brain disorders.49 It mayhave a role for treating Alzheimer’s disease.50

Lecithin, composed of a phosphate group,choline, fatty acids, glycerol, glycolipids, triglycer-ides, and phospholipids including phos-phatidylcholine, phosphatidylethanolamine, andphosphatidylinositol, is a common source of oralphosphatidylcholine. Phosphatidylcholine is alsoavailable in an injectable form. Injectable phospha-tidylcholine is not approved by the FDA. Phospha-tidylcholine, however, is a component of severalFDA-approved intravenous drugs.51 Injectablephosphatidylcholine can be obtained throughcompounding pharmacies, the Internet, or over-seas (Mesoestetic, Limited, Barcelona, Spain).

In the Russian literature in particular, there aremany reports on the positive effects of phosphati-dylcholine on lipid profiles and cholesterol levels. Ithas been used oversees to treat liver disease,including hepatitis, cirrhosis, fatty liver, and drug-or toxin-induced liver damage.52 In the UnitedStates, basic science research has shown positiveeffects of phosphatidylcholine on cholesterollevels, alcohol-induced mitochondrial injury,alcohol-induced hepatocyte apoptosis, and liverfibrosis.52–56

In Europe, intravenous phosphatidylcholine,marketed under the brand name Lipostabil, manu-factured by Sanofi-Aventis Group (Paris, France).It comes in 5 cc ampoules. Each ampoulecontains: 70% phosphatidylcholine (250 mg),unsaturated fatty acids, vitamin B6, adenosine-50-monophosphoric acid, nicotinic acid, andbenzyl alcohol (preservative). Sanofi-Aventis alsooffers an oral form called Essentiale. In 1966,Kroupa reported the use of Lipostabil to preventfat embolism.57 Lipostabil has been shown torestore the normal equilibrium between low-density lipoprotein (LDL) and high-density lipopro-tein (HDL) levels in the blood and to promotecholesterol transport.49 Based on these findings,in Europe, Lipostabil is indicated for treatinghyperlipidemia, atherosclerotic disorders, diabeticangiopathies, angina pectoris, postmyocardialinfarction, hypertension of sclerotic origin, andthromboembolism pre- and postoperatively.58,59

The aesthetic applications of injectable phos-phatidylcholine evolved from the oral and intra-venous use of phosphatidylcholine for treatinghyperlipidemia and related disorders. In 1988,Maggiori reported the first use of phosphatidyl-choline for aesthetic purposes when he used itto treat xanthelasmas.60 Following Maggiori’sreport, the use of phosphatidylcholine injec-tions expanded to include subcutaneousinjections.

INJECTION LIPOLYSIS USINGPHOSPHATIDYLCHOLINE TO REDUCESUBCUTANEOUS FAT

In 2001, Rittes, a physician practicing in Brazil, firstreported in the English dermatologic literature onthe subcutaneous injection of phosphatidylcholineto reduce the size of infraorbital fat pads.61 Thirtypatients were studied. The longest follow-up was2 years. Twenty milligrams of phosphatidylcholinewere injected into the central, medial, and lateralfat pads; the distribution per fat pad varied accord-ing to the patient’s needs. The patients receivedadditional treatments at 15-day intervals if bulgingfat pads persisted after the first treatment. Twopatients received four treatments; five patientsreceived three treatments. Twelve patientsreceived two treatments, and 11 patients receivedone treatment. Improvement was noted by obser-vation, and cosmetic improvement was noted in allpatients. After treatment, patients noted mildburning that lasted 15 minutes. Edema of theentire lower eyelid lasted approximately 72 hours.There were no reported recurrences.

Other clinical reports soon followed. In 2004,Ablon and Rotunda reported on the use of phos-phatidylcholine for treating lower eyelid fat pads;7 of 10 patients demonstrated a clinical benefit.62

In 2006, Hasengschwandtner reported on thetreatment of 441 patients by injection lipolysis.63

The patients received a maximum of 2500 mg ofphosphatidylcholine per session in a singlespecific area; the number of sessions varied.One injection contained 0.5 cc of mixture ata depth of 12 mm and 1.5 cm apart; the mixtureconsisted of phosphatidylcholine 50 mg/mL,NaCl as dilutant, buflomedil (vasodilator) andB-vitamin complex. Pre- and post-treatmentcircumferences were measured and before andafter photographs taken. Post-treatment assess-ment was made at 8 weeks. Fifteen percent ofpatients were satisfied after one treatment and72% after two treatments. The average circumfer-ential reduction was 3.7 cm on the upper belly,3.9 cm on the lower belly, 1.9 cm on the hips,and 1.6 cm on the upper arm.

SAFETYOF SUBCUTANEOUS INJECTIONOF PHOSPHATIDYLCHOLINE

Phosphatidylcholine has been used for manyyears for preventing and treating fat embolism(intravenous), severe liver failure (oral and intrave-nous), and in surfactant preparations. Using intra-venous and oral phosphatidylcholine preparationsfor these indications, no significant toxicity isnoted even at relatively high doses. The known

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systemic adverse effects of subcutaneous injec-tion of phosphatidylcholine are cholinergic GIeffects including nausea, increased salivation,and abdominal pain. Most practitioners recom-mend limiting the dose to 2500 mg per treatmentsession to minimize these effects. These symp-toms are similar to the known effects of oral andintravenous phosphatidylcholine-containing prep-arations. Subcutaneous injections of phosphati-dylcholine are associated with burning, urticaria,erythema, swelling, ecchymosis, and pruritis.64,65

Injections placed too superficially may cause skinulceration.

One potential outcome after subcutaneousinjection with phosphatidylcholine is an efflux offree fatty acids. Free fatty acids are known tocause experimental myocardial infarction indogs, fat embolism, and steatosis of the liver(A Matarasso and J Kral, personal communication,2002). Additional concerns center on the potentialcreation of high levels of lysophosphatidylcholine,the natural degradation product of phosphatidyl-choline. Lysophosphatidylcholine is known tocause hepatic cholestasis, liver enzyme elevation.and intravascular hemolysis.66

Serious allergic reactions, such as anaphylaxis,have not been reported. Experienced medicalpractitioners report local adverse effects such aspain, hematoma, edema, and nodules, which aremild and well tolerated; systemic adverse effectsare rare (Rittes, 2007). In Hasengschwandtner’s2006 report, no serious adverse effects or compli-cations were noted. In 31 patients who had normalblood work within 6 months before treatment, totalbilirubin and gamma glutamyl transferase werechecked 5 days and 8 weeks after treatments. Allblood values were within normal limits. All patientsreported a small-to-medium level of pain, swelling,and erythema. Deep hematomas also were noted.Patients additionally reported soft stools, and fourreported menstrual bleeding outside of the normalmenstrual cycle. The skin overlying the treatedarea was noted to be firm and excess skincontracted.

In 2006, Duncan and Chubaty reported onsafety data for injection lipolysis using phosphati-dylcholine-based formulas.67 Data were collectedfrom 75 physicians practicing injection lipolysis in17 countries; 17,376 patients were treated. Therewere no reports of bacterial or atypical mycobac-terial infections, skin ulceration, dermatitis, orchronic skin irritation. Disappointment with theresult was noted in 12% of patients. Transienthyperpigmentation (0.015%), allergic reaction(0.0003%), and persistent pain beyond 2 weeks(0.015%) were infrequent.

MECHANISMS OF LIPOLYSIS

Although some reports show a reduction in fatdeposits after subcutaneous injection of phospha-tidylcholine and deoxycholate, the mechanism bywhich this would occur is not understoodcompletely. Furthermore, it is not known whetherit is the phosphatidylcholine or deoxycholate aloneor a combination of both or neither that isproducing the clinical effect. Theoretically, severalmechanisms could exist alone or in combination.

For the purposes of understanding its possiblemechanism of action in fat reduction, it is importantto understand the multiple roles of phosphatidyl-choline in the human body. The first is its role inthe transport and emulsification of dietaryfat.48,68–70 Phosphatidylcholine is found in bileand acts to promote the emulsification of dietaryfat. A necessary step in the digestion of dietary fatoccurs when fat globules, which are insoluble inwater, are broken down into smaller sizes so thatwater-soluble digestive enzymes can act on thesurface of the fat globule. The phosphatidylcholinemolecule has a polar (water-soluble) moiety,choline, and a nonpolar (fat-soluble) moiety, thefatty acids. The fat-soluble portion of the phospha-tidylcholine dissolves in the surface layer of the fatglobule, with the polar portion projecting outwardinto the aqueous environment.

The polarity of phosphatidylcholine is importantfor several reasons. First, because the polar headof the phosphatidylcholine is very soluble in theaqueous fluid, the interfacial tension of the fatglobule is decreased, and the fat globule can bebroken up into minute particles by the normalagitation that occurs during peristalsis of the intes-tine. In the digestion of fats, this emulsification offat can increase the total surface area of dietaryfat by 1000 times. Thus, intestinal lipases can actupon a much larger surface area than would beavailable without emulsification. Intestinal lipasesbreak fat down into monoacylglycerol (glycerolwith one fatty acid) and fatty acids.

Second, the polarity of phosphatidylcholinecontributes to the three different chemical formsof phosphatidylcholine. The first form is the lipidbilayer, with the hydrophobic tail in the middle ofthe lipid bilayer. The second is a vesicle or lipo-some, where the lipid bilayer or monolayer formsa circle creating a hydrophilic interior core. Thethird is a micelle, where the phosphatidylcholineexists in a single layer, with the hydrophilic headsprojecting outward, creating a hydrophobic core.Triglycerides and fatty acids are solubilized andtransported in the hydrophobic core of the phos-phatidylcholine micelle.

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The role of phosphatidylcholine in cholesterolmetabolism is also important. Phosphatidylcholineis found in HDL, the apolipoprotein that carriesfatty acids and cholesterol from the peripheraltissues to the liver. HDLs are so called, becausethey carry the highest percentage of protein.HDLs exist as spheres with a hydrophic core thatis capable of storing cholesterol esters. As morecholesterol is accumulated, the HDL increases insize. Thus, in evaluating risk of atheroscleroticheart disease, it is the ratio of large HDL particles(those that contain more cholesterol) to total HDLthat is important.

THE ROLE OF DEOXYCHOLATE(DEOXYCHOLIC ACID)

Phosphatidylcholine alone is very viscous and thusnot amenable to injection. For this reason, and asis the case with other injectable pharmaceuticals,sodium deoxycholate, a bile salt, is added to solu-bilize the phosphatidylcholine, thus making thephosphatidylcholine suitable for injection. Debateexists as to which of the injected chemicals isresponsible for the noted clinical results in patientstreated for subcutaneous fat reduction. Untilrecently, it was assumed that the active ingredientin the injectable preparations used for subcuta-neous fat reduction was the phosphatidylcholine.Recent data, however, suggest that the sodiumdeoxycholate also may be an active ingredientthat causes cell lysis, which may lead to a reduc-tion in subcutaneous fat, and not just a solubilizingagent.71 In addition, deoxycholate without phos-phatidylcholine has been shown to reducelipomas.72 This is further evidence that deoxycho-late may play an active role in reducing subcuta-neous fat.

Brown discussed the possible role of deoxycho-late in injection lipolysis in a 2006 publication.73

Brown believes that at the concentration used inLipostabil, deoxycholate would exist as a monomerif injected alone. When injected with phosphatidyl-choline into the subcutaneous tissue, four distinctforms of deoxycholate could exist: micelles, vesi-cles with excess deoxycholate present as mono-mers, and crystals. It is not known which of theseforms is acting on the adipocyte. Brown theorizesthat several possibilities could exist:

Deoxycholate in vesicle form with excessmonomers; the monomers lead to cellularnecrosis

Deoxycholate is presented in micelle form,which could result in a mobilization of fatfrom the adipocyte

Crystals that are known to be damaging tocells

ADDING ITALL UPçPOSSIBLEMECHANISMSOFACTION

The current theory is that the clinically observedreduction in subcutaneous fat after injection lipol-ysis is caused in part by cell wall destruction ofthe adipocyte followed by a reduction in adipocytefat. It is possible that either the phosphatidylcho-line or deoxycholate or both could be responsiblefor cell wall destruction. Duncan has shown adipo-cyte cell wall destruction after injection withcompounds containing phosphatidylcholine anddeoxycholate.74 It is thought that the disruptionof the adipocyte cell membrane primarily is causedprimarily by the deoxycholate contained in themixture, although phosphatidylcholine alone hasbeen shown to disrupt cell walls.75

Following cell wall destruction, there are severalpossible mechanisms that could lead to reducedvolume of fat stored in adipocytes. One possibilityis the injected phosphatidylcholine acts to emul-sify the stored triglycerides, which then are trans-ported to the liver, where they are metabolized.Duncan showed in one patient injected with phos-phatidylcholine containing formula that, afterbiopsy, the treated area showed cell wall disrup-tion and a reduction in adipocyte diameter. Inflam-mation and new collagen deposition also werenoted. Because fat is stored in adipocytes in theform of triglycerides, it is possible that the smalleradipocyte diameter is caused by transport oftriglycerides and fatty acids out of the adipocyte.Theoretically, phosphatidylcholine could dissolvethe triglycerides and transport them elsewhere asmicelles. The inflammation and new collagendeposition Duncan noted could contribute to theskin tightening noted in treated subjects. Othersspeculate that after the cell membrane of theadipocyte is disrupted, lipase is activated andbreaks down the intracellular fats.

Another possibility is that even if cell walldestruction does not occur, the injected phospha-tidylcholine activates lipases, which break downtriglycerides to fatty acids, which then are trans-ported as lipoproteins. Phosphatidylcholine alsomay exert its effect by stimulating beta-receptorsor inhibiting alpha-2 receptors, thus producingincreased lipolysis activity. Lastly, concentratedamounts of phosphatidylcholine injected subcuta-neously could act to emulsify fat, allowing tissuelipases to hydrolyze fat, producing glycerol andfree fatty acids.

CONTROVERSIES IN INJECTION LIPOLYSIS

Limited scientific data are available about injectionlipolysis. Medical professionals and organizations

Mesotherapy and Injection Lipolysis 189

including the American Society of PlasticSurgeons (ASPS) and the American Society forAesthetic Plastic Surgery (ASAPS) have criticizedthe clinical use of phosphatidylcholine and deoxy-cholate for subcutaneous fat reduction. Amongother reasons, there is concern that the clinicalapplication of subcutaneous injection of phospha-tidylcholine and deoxycholate preceded IRB-approved studies. Both the ASPS and the ASAPShave issued press releases warning the generalpublic to be wary of mesotherapy until safety andefficacy have been proven.76,77 The ASAPS issueda position statement that contains recommenda-tions for aesthetic society members regardingmesotherapy and injection lipolysis. In the 2007position statement, members were advised to‘‘refrain from adopting these treatments until theresults of the Aesthetic Surgery Education andResearch Foundation (ASERF)-sponsored studyare available to provide proof of safety and effi-cacy, or lack thereof’’.78

Furthermore, the products remain unapprovedby the FDA for subcutaneous injection. Lipostabilis not a registered drug in the United States andis not approved by the FDA in the United Statesfor any use. The FDA’s current position is that Lip-ostabil is a new drug under the Federal Food, Drugand Cosmetic Act and thus requires that a newdrug application be filed with the FDA beforemarketing. In addition, no pharmaceutical isapproved by the FDA for use in mesotherapy orinjection lipolysis for reduction of subcutaneousfat. Practitioners are cautioned to inquire with theirmalpractice insurance carriers to determinewhether mesotherapy or subcutaneous injectionsusing non-FDA approved medications is coveredunder the terms of their malpractice insurancepolicy. The use of any of these agents for non-FDA approved indications such as localized fatreduction may place the practitioner at some legaland regulatory risk.79,80

The extensive marketing of nonapproved prod-ucts and treatments is a source of concern in themedical community. Subsequent to the firstreports in 2001 on the use of Lipostabil in aestheticapplications, Lipostabil has been marketed aroundthe world under many names including Flabjaband Lipomelt. Other formulas containing phospha-tidylcholine and deoxycholate for subcutaneousinjection, such as Lipodissolve, also have beenmarketed aggressively in the United States. Themarketing by businesses promoting these prod-ucts and procedures preceded FDA-approvedtrials to evaluate the safety and efficacy of thesetreatments; as such, this marketing was donewithout documentation of the results claimed orthe identification of potential complications. In

2007, the Kansas State Board of Healing Arts, ina ruling that later was overturned, banned allcommercial use of Lipodissolve, a compound con-taining phosphatidylcholine used to reduce subcu-taneous fat. The board voted to allow the use ofthe drug only as part of FDA-sanctioned clinicaltrials under an investigational new drug applica-tion.81 The company promoting Lipodissolve sincehas declared bankruptcy. Recently, the nameLipodissolve was trademarked by a nonphysicianwho offers courses on the lipodissolve technique.Furthermore, in the United States, it is illegal toadvertise the use of an unapproved product oran off-label use of an approved product. Althoughthe enforcement of these regulations may seemlax, practitioners are exposed to enforcementactions by the FDA, actions by state medicalboards, and other sanctions.

To date, there are no published IRB-approvedtrials evaluating the subcutaneous injection ofphosphatidylcholine and deoxycholate. One suchstudy recently began and, as of this writing, hasseveral patients enrolled. In early July 2008,Dr. V. Leroy Young, after obtaining an investiga-tional new drug (IND) permit from the FDA, beganan IRB-approved study evaluating the effects ofthe subcutaneous injection of phosphatidylcholineand deoxycholate (TM Pfeifer and Young VL,personal communication, 2008). The study issponsored by the Aesthetic Surgery Educationand Research Foundation of ASAPS. It is overseenby the Western IRB and the IRB of WashingtonUniversity. Early study results are anticipated inMarch 2009.

SUMMARY

Localized deposits of excess adipose tissue andindeed obesity can be medically dangerous andpsychologically distressing to patients. Withrespect to mesotherapy as a method of body con-touring, more studies are necessary before advo-cating this as a safe and effective treatment.Physicians practicing injection lipolysis areworking to elucidate the safety and efficacy ofthe subcutaneous injection of phosphatidylcholineand deoxycholate.82 Finally, establishing stan-dards of practice to ensure patient safety is anabsolute priority for these physicians.

The lipolysis responsible for reduced subcuta-neous fat after injection lipolysis may result inincreased levels of free fatty acids and glycerol inthe bloodstream. To ensure the safety of injectionlipolysis with phosphatidylcholine and deoxycho-late, it would be prudent to know the products ofdissolution, whether free fatty acids are releasedinto the patient’s bloodstream, whether the

Matarasso & Pfeifer190

injected chemical is absorbed into the blood-stream, the effects on the liver and other organs,the appropriate dose, among other things. More-over, although the intracellular contents of theadipocyte can be reduced, the fate of the adiposecell membrane and how that may affect recur-rence are unknown.

When skillfully applied to the appropriatepatient, the results of body-contouring proceduresare pleasing to the plastic surgeon and patient.The promise of a simple, permanent method ofreducing subcutaneous fat is obviously veryappealing. In view of cultural attitudes that valuea trim physique and youthful appearance and therise in the number of overweight individuals insociety, it is likely that the demand for body-con-touring procedures including liposuction and otherpotential methods such as mesotherapy and injec-tion lipolysis will increase. Physicians must striveto evaluate new treatment modalities throughrigorous scientific study while at the same timekeeping an open mind about potential new thera-pies that could benefit patients.

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