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Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. International Journal of Advanced Pharmaceutics www.ijapjournal.com MESOTHERAPY – A REVIEW * P. Latha and K.R.Vandana *SreeVidyanikethan College of Pharmacy, Tirupati-517102, Andhra Pradesh, India. ABSTRACT Mesotherapy involves multiple intradermal or subcutaneous injections of a mixture of compounds (plant extracts, homeopathic agents, pharmaceuticals, vitamins, and other bioactive substances) in minute doses, using very fine gauge needles, to treat medical (mainly local) and cosmetic conditions. The proposed mechanism of action of mesotherapy is that solutions that are injected intracutaneously remain in the area longer than they would if delivered via deeper injection because they are cleared more slowly by the general circulation. In addition, it is felt that these superficially injected solutions continue to penetrate into the deeper tissues. The more superficial the injections, the longer the solution remained in the area. Mesotherapy proponents base their claims that mesotherapy is safer than liposuction on the fact that mesotherapy is a nonsurgical procedure. However, liposuction is FDA-approved and -regulated, while many uncertainties surround mesotherapy. Keywords: Mesotherapy, mechanism of action, Mesotherapy Injection Techniques. INTRODUCTION The term 'meso' also means 'middle' and 'mean', hence variably explained with reference to the injection route (into the middle layer of skin or 'intradermotherapy') and the mean dose of the medication used (dose in between allopathy and homeopathy). Mesotherapy involves multiple intradermal or subcutaneous injections of a mixture of compounds (plant extracts, homeopathic agents, pharmaceuticals, vitamins, and other bioactive substances) in minute doses, using very fine gauge needles, to treat medical (mainly local) and cosmetic conditions. The term “mesotherapy” was suggested by Dr. Pistor (Father of mesotherapy) in1958. The prefix mesooften raises some questions. For the author, his therapy was only effective on derivatives of the mesodermis, however, the effect on the tissues of the mesodermis is so important that these treatments deserved the global name of mesotherapy (vessels, tendons, conjunctive tissues) [1]. Corresponding Author:-P. Latha Mesotherapy does not denote a treatment of any condition in particular; it simply describes a method of drug delivery. Mesotherapy is a medical technique 1. Performing it requires medical knowledge and practice 2. An accurate diagnosis is essential, using clinical and instrumental(?) tests 3. The efficacy of the treatment is not linked to the amount of drug given but to the choice of drug 4. This requires precise pharmacological criteria Mesotherapy requires 1. A sensible indication 2. A correct clinical assessment 3. Flawless technology 4. Proper technique 5. Suitable drug combinations Email:[email protected] pg. 19 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. Mesotherapy is one of many treatment modalities that we should master in order to be accomplished cosmetic medicine practitioners. MECHANISM OF ACTION It has been suggested that the skin acts as a natural time-release system when drugs are injected by mesotherapy. The proposed mechanism of action of mesotherapy is that solutions that are injected intracutaneously remain in the area longer than they would if delivered via deeper injection because they are cleared more slowly by the general circulation. In addition, it is felt that these superficially injected solutions continue to penetrate into the deeper tissues. The more superficial the injections, the longer the solution remained in the area [2]. Mesotherapy Injection Techniques Each session of mesotherapy involves superficial injections of medications using specialized short needles and specific techniques directly over the sites of the affected structures. Several hundred injections are given, though the number may vary depending upon the indication. In general, 1-3 sessions in acute cases, such as sports injuries and 10-15 with maintenance sessions every 6 months or a year for chronic conditions such as ''cellulite'' may be required. Commonly three different techniques are used. 1. Point by point First described by Dr. Pistor, involves injection of 0.02 ml to 0.05 ml of drug solution perpendicular to the skin (4 mm deep), given 1 cm to 2 cm apart. 2. Nappage (French for "covering") Involves more superficial (2 mm deep) injections with a 4-mm needle, covering a large area. Injections are given at a 45 degree angle from the skin while applying light, constant positive pressure on the plunger, the practitioner rapidly flicks the wrist (mimics shaking a salt shaker or the action of a sewing machine). At each site, a drop of solution is introduced. Relatively, this is a more discomforting procedure to the patient [3]. 3. Epidermic The most superficial (1 mm deep) of all the techniques in which the basal layer of skin is not penetrated. Needle size of 27 to 31 gauges is used with the bevel oriented away from the skin and dragged along with light, positive pressure applied to the plunger. It is done in a grid pattern at 1-cm intervals over the entire affected area. Multiple injections of small doses of medications, in precise locations, in a single sitting are highly demanding to the therapist. To overcome this difficult task, many practitioners in Europe and South America use a device called 'mesogun'. The benefits of mesogun include faster injections, precise dose delivery, consistent depth of penetration and more comfort for the physician and patient. Some experts use a special technique [4]. USES The medical benefits include improved blood flow to the area, dissolving excess fat deposits, removing fibrotic, hardened connective tissue and improving lymphatic drainage. It is highly effective in treating arthritis, joint and liver disorders. By puncturing the skin and injecting a little medication right below the surface in the affected area, (the needles used are only between 0,16 and 0,51 inches long), the substance does not have to pass through the blood, the liver and the stomach, resulting in the desired effects being far more powerful and quickly obtained. Mesotherapy in cellulite patients Celluliteis a condition where collections of fat push against the connective tissue causing cosmetically unacceptable lumpy, dimpled appearance of skin resembling cottage cheese. Cellulite treatment Mesotherapy is a technique that can be used to treat cellulite. Keep in mind the following: There are four stages in the treatment for cellulite 1. Reducing lipoedema Use benzopirone plus procaine 2. Restoring efficient microcirculation Use derivatives of the flavonoids, which offer a particularly beneficial vasculo-protective effect Pentoxiphylin Vitamin C is essential for neutralizing the effects of free radicals generated in the newly oxygenated tissue Procaine 3. Lipolysis use Theophylline + Caffeine + L-Carnitine + Yohimbine+ Procaine 4. Restructuring and protecting the connective tissue Silicium (Conjonctyl) stimulates the regeneration of connective tissue A cellulite mesotherapy treatment requires at least 3 months‟ time. In treating cellulite, for better clinical results, it is important to use a combination of different techniques, including mesotherapy. To be effective, these techniques have to work first on the extra cellular matrix, the microcirculation (arteriolar, capillary, venous) and the lymphatic system, and finally, on the fat tissue [5]. pg. 20 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. The approved use for pentoxifylline is for the treatment of intermittent claudication. The drug improves microcirculation by decreasing the blood‟s viscosity and by improving erythrocyte flexibility. Pentoxifylline has been shown to increase leukocyte deformability and inhibit neutrophil adhesion and activation. Tissue oxygen levels have been shown to significantly increase with therapeutic doses of pentoxifylline in patients with peripheral arterial disease. Mesotherapists believe that by increasing microcirculation of localized tissue beds, the elimination of metabolic waste is facilitated. Injecting pentoxifyllinemesotherapeutically is believed to exercise the drug‟s therapeutic effect for a longer period of time compared to other routes of administration [6]. For cellulite treatment and localized fat reduction, practitioners use compounds that efficiently remove fat from cells and move this fat into the general circulation, to be burned during metabolism or excreted. Phosphatidlycholine, or lecithin, is one such compound, and is widely used. Caffeine, L-carnitine and the asthma drug aminophylline are other compounds used for fat reduction. Natural compounds such as artichoke stimulate lymphatic flow to remove fat. Tiratricol, a drug that was originally developed to treat some types of thyroid cancer, is also an efficient fat burner. Hyaluronidase and collagenase disintegrate the bands of fibrous tissue formed between fat lobules in cellulite. Glycolic acid exfoliates the skin (peels). Vitamin A regulates cell turnover of skin and keratinization; Vitamin C enhances the synthesis of collagen and reduces hyperpigmentation as it inhibits melanin production; Vitamin E, an antioxidant, aids in anti-aging of the skin; Vitamin K affects clotting mechanisms and thus regulates the microcirculation of the skin; DMAE cause myofibril contraction and smoothen the lax skin; while trace elements are important for regulating turnover and repair of skin cells. Mesotherapy provides a route of administration that allows for delivery of low doses of medication with minimal complications. In Europe and South America, many practitioners choose to use mesotherapy guns for injections. The benefits of using mesotherapy guns include: 1. Speed: Faster than manual injections 2. Precision: Delivers precise doses of medication per injection 3. Consistency: Achieves the same depth of penetration on each injection 4. Comfort: More comfortable for the physician and patient Unwanted fat removal and skin rejuvenation Mesotherapy, when used for skin rejuvenation, infuses the dermis with potent vitamins and anti-oxidants to rejuvenate and revitalize the skin. The results are skin that is firm, radiant, youthful and glowing. Initially a series of 2-4 treatments are performed a week apart. Results are maintained by twice a year touch-up sessions. When the correct cocktail is used and injected into the dermis it is an effective skin strengthener. The vitamins stimulate collagen and hyaluronic acid stimulates new cell growth. Simply by puncturing the skins surface blood growth factors are released which stimulate new cell formation. The fat beneath the skin melts and shrinks the fat cells in the Scarpa‟s fascia layer. The fat dissolves and is excreted by the kidneys. A series of treatments (5-15) is given, spaced one week apart. Results are considered permanent as long as the patient adheres to a proper nutrition and exercise regimen. Occasional touch-ups may be required [7]. Many patients who develop unevenness, divots, or lumps after undergoing liposuction find that these areas can be successfully treated with Mesotherapy. The scar tissue that forms under the skin after liposuction is directly targeted and dissolved. Doctors are even combining Mesotherapy withEndermologieto maximise the results. Most of the conditions treated such as cellulite and wrinkles have multifactorial causes and due to this it is necessary to use multiple ingredients to treat the condition effectively. For mesolifts or facelifts using mesotherapy, several drugs are available for injection under facial skin to improve skin tone and reduce the appearance of wrinkles [8]. Estrogen derivatives such as 17 B-estradiol stimulate new collagen formation. Glycosaminoglycans are a natural compound that forms linkages between collagen fibers. Naturally occurring alpha hydroxy acids such as glycolic acid are also used for mesolifts. The drugs found to be very effective in the elimination of unwanted fat deposits and skin rejuvenation include phosphatidylcholine (PC), L-carnitine, aminophylline, hyalorunidase, collagenase, glycolic acid, retinoic acid, multivitamins (A, D, E, K), trace elements [minute quantities of zinc, copper, selenium, chromium and manganese], an acetylcholine analog dimethylaminoethanol (DMAE), lidocaine etc. Mechanism The proposed mechanisms for the various compounds in removal of unwanted fat are as follows. PC has lipolytic activity by affecting the permeability of the adipocyte membrane and subsequent fat mobilization. Some add small quantities of sodium deoxycholate pg. 21 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. to increase the fat-dissolution effectiveness of PC through disintegration of adipocytes. Thyroid preparations, aminophylline and isoproterenol are supposed to stimulate insulin release which helps in breaking down of fat cells [9]. Pain Mesotherapy was traditionally employed for pain relief, in conditions like fibromyalgia, gout, headache, neuralgia,low back ache, sports injuries (i.e., sprains, strains, bursitis, tendinitis),and dental procedures.The procedure involves multiple small volume injections of an analgesic i.e. NSAID (commonly piroxicam or ketorolac), surrounding the painful area e.g. inflamed tendon. Skeletal muscle relaxants like baclofen or diazepam are also commonly co-administered. Another widely employed drug in France, for chronic pain disorders, is salmon calcitonin (sCT) which is already used in conventional medicine as an analgesic in painful bone disorders ranging from osteoporosis to cancer [10]. NSAID The subjects were divided into three groups. The first group received intraepidermic papules of a diluted NSAID, The second group received subcutaneous injections of the same solution using 4mm needles, and The third received deep intramuscular injections of the same solution. At 1 and 3 hourspost injection, venous blood draws were performed to determine serum levels of the NSAID. It was found that uniformly, the shallower the injection, the lower the level of the substance present in venous circulation at both 1 and 3 hours post injection. Alopecia Injections of minoxidil, finasteride, lidocaine, multivitamins, T3/T4 are used in treatment of alopecia. In house publications and company brochures suggest that injections of "cocktails" of natural plant extracts, homoeopathic agents, vasodilators, finasteride and minoxidil and vitamins are carried out with a mesogun once in 2-4 weeks. Of these, only minoxidil and finasteride have an established role in the management of pattern hairloss. Both the mechanism of action and the efficacy of other agents are not established and are doubtful. Further, a recent publication of guidelines on esthetic practices in Singapore listed mesotherapy as a List B procedure (List B procedure indicates procedures with low or very low evidence or local medical expert consensus that procedure is neither well-established nor acceptable) [11]. In view of these data, the current position on the use of mesotherapy in pattern hairloss can be summarized as follows. 1. Data on its safety and efficacy in pattern hairloss have not been adequately and critically evaluated and documented in proper, peer-reviewed clinical trials. 2. Data evaluating the rationale and pharmacology of the combination of herbal and allopathic medicines used are not adequate. There are no clear-cut guidelines on the dosage and efficacy of the products. No Needle Mesotherapy It is discomfort for the patients as needles are injected 1cm apart in the entire area. Another way to incorporate mesotherapy into a spa or salon without a nurse or a doctor is by using the new no-needle mesotherapy devices. No-Needle Mesotherapy Equipment (Beauty Skin Equipment) This needle free meso therapy beauty instrument is a new design for skin care and fat loss. No-needle Mesotherapy System Characteristics: 1. No-needle mesotherapy works more effective by customizing the cosmetic solution according to characteristic of specific skin. 2. No-needle mesotherapy uses the latest bio-tech production technology to select the small molecular weight ingredient that can be rapidly absorbed by skin. 3. No-needle mesotherapy features over 1000 times of absorption rate comparing with ordinary cosmetic products by using ultra micropenetration technology with which effective nutrimental ingredients can directly reach the most demanding part of the skin. 4. Mesotherapy produces long lasting efficacy, thanks to th unique bio-packet technology that carries the biologically active ingredients into skin cells via capillaries, and gradually release them to continuously stimulate the cell rejuvenation for lively and youthful skin [12]. Treatment Range: 1. Dissolve fat quickly 2. Remove wrinkle safely 3. Reduce cellulite 4. Skin whitening and spots removal 5. Complement water and keep moisture 6. Restore skill Product Description No-needle mesotherapy beauty skin equipment is a high-tech and effective alternative to the injection based mesotherapy method using pulses of electrical energy especially designed to relieve congested tissue, ours has the following obvious functions. Four wave shape for pg. 22 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. individualtreatment:Skin rejuvenation, moisture locking, wrinkles removal and freckles reduction, as well fatness dissolving, cellulite treatment etc according to different drug injection. Another four Chinese traditional physical therapy:Acupuncture, cupping, hypnosis and massage Delegated to nurse or technician Pain free with no swelling or bruising Standardized drug cocktails Average treatment time 30 minutes Body and face treatments. Noneedle Mesotherapy Equipment is high-effect, woundless and safe treatment, completely removes the traditional needle and micro-needle injection. It takes electrophoresis, (introduced into Europe markets in 2000 by the Italy company, Microlab Biomedical, got FDA approval in 2005, Nobel Prizes Winner in Chemistry in 2007), uses the electroporation and electroosmosis, by orientation, layer-oriented, ration to supply nutrition to the deep-seated cells, assist to melody the muscale, lymph drainage, promote metabolism, lymph and blood circulation, so as to decrease, wrinkles, whiten skin and keep moisture, improve cellulite, quicken fat dissolving and weight loss. Comparing it with the single skin care products, effectively absorb products higher 2000 times, thoroughly solve the problem of products only staying in the epidermis, can keep skin young for a certain term and shorten the period of treatment. No-needle Mesotherapy is truly the brightness of beauty equipments in 2008 [13]. FEATURES Solve 3 troubles in beauty field 1. With no use any injectors, by orientation, layeroriented, ration, to transmit many kinds of nutrition into deep-seated cells, let skin whitening, wrinkle and freckle removal and skin thinning at one-step. 2. The absorption effect is higher over 2000 times than the traditional skin care products. 3. It can be designed by the customers original liquid containers, let the equipment match with the skin care products, very special. Features 1. Greatly enhance penetration of natrual substance into skin 2. RF enhances the face contour result, which is solidified by LED 3. Provide wide applications according to different cosmetic products 4. Touch screen, set operation time freely 5. Upgradable platform Mechanism FUSION MESOTHERAPYis a new concept in non-invasive aesthetic medicine. A new mesotherapy approach based on breakthrough systems and products. Fusionmesotherapy(needle-free)isa radio frequency (RF) based device.It enhances the transdermal transport of topical products, through the epidermis to the dermis. The radiofrequency (RF) produces a cellular electroporation reducing the permeability of the skin and opening cellular pores. At the same time the radiofrequency (RF) increases the skin temperature of 5 to 7ºC to stimulate the collagen synthesis and skin tightening. Fusion mesotherapy, consists in combining sub-cutaneous injector (conventional mesotherapy MESO-PEN device) and the radiofrequency (RF) device. This technique improves the effectiveness of injected products and the results. It has been demonstrated by clinical study to be very effective for lipolysis offering a real alternative to plastic surgery lipoplasty and lipo-lasers [14]. Main indications: Skin rejuvenation, expression wrinkles, wrinkles, skin tightening, whitening, acne, anticellulite, lipolysis, sport medicine etc. Electroporation and Electroosmosis Electroporation: Directly act on the skin, instantly enhance skin tissue penetration. Under the function of electroshock, there will be formed holes in the lipid mobilization of cells, at the same time, the hydrophile molecule which have not been absorbed originally can penetrate into cells inner. Once the holes forming, withing several seconds to several minutes, it will keep the opening state according to the length of electroshock. Electroosmosis: Mainly act on the substance molecule which will be dispersed, help it freely to penetrate into skin inner. Same quality electric charges are mutual repulsion, so it can throw positive current onto positive nutrition molecule, push untritin molecule into skin tissues. At the same time, the neutral molecule also will penetrate into skin inner [15]. ADVANTAGES OVER OTHER THERAPIES When taken orally, the liver and stomach will destroy part of the drugs and other parts will diffuse everywhere in the body, which can cause undesired side effects and only a small amount will arrive in the required area. Furthermore, the amount of medication, either conventional or homeopathic, to be used can be greatly reduced; the quantity injected can be as little as only 1% of the quantity used in normal treatments, which again reduces the side-effects and also avoids the body becoming resistant to certain drugs. The combination of vitamins, herbal products and medication that is injected is tailored specifically for each patient to optimize results. Many factors are taken into consideration to determine the most effective combination including genetics, gender,liposuction, type of fat, age and medical history [16]. pg. 23 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. The FDA and Mesotherapy: A Shaky Relationship The FDA and mesotherapy have had a shaky relationship throughout the years. Mesotherapy was a popular procedure in Europe long before it came to the United States. However, since it arrived in the US in the 1990s, it has been riddled with doubt towards its effectiveness and safety. The Food and Drug Administration, or the FDA is the organization that approves the food and drugs that we use and assures that they are safe for use. It is important to note that FDA and mesotherapy have not come to common terms with each other - the FDA has not approved mesotherapy, although it has the support of some very influential dermatologists [17]. Many of the drugs used in mesotherapy were not created especially for their mesotherapeutic purposes. For example, the commonly use drug in mesotherapy injections, Aminophylline, was originally approved as a bronchodilator drug for those with several lung conditions, such as chronic bronchitis or emphysema. It is used in mesotherapy as it is proven to help improve blood flow in patients with respiratory problems and the hope is that it will do the same with those who have cellulite. Yohimbine is a commonly used drug approved by the FDA, but not for mesotherapy. It was actually originally used to treat erectile dysfunction. It works in a manner similar to aminophylline, as it causes vasodilation, thus increasing blood flow. It is believed that increased blood flow reduces fluid retention, and reduced fluid retention can possibly lead to less cellulite [18]. Procaine is another very popular drug used in mesotherapy. It is a local anesthetic also known as novocaine and is used to relieve the burning and itching sensations that sometimes come with mesotherapy injections. Other anesthetics used in mesotherapy include lidocaine and marcaine, both which are also FDAapproved. They are used in hospitals and are injected in patients with pain, the same purpose it holds in mesotherapy. However, anesthetics can be deadly when the proper precautions are not taken, so make sure any local anesthetic that is injected during mesotherapy is under the supervision of a certified doctor or nurse. Other compounds do not have FDA-approval for any sort of use, as they are not considered drugs and are thus beyond the scope of the FDA„s regulation. This includes vitamins and minerals, such as those found in the local pharmacy. Mesotherapy practitioners often use liquid solutions of these compounds and inject them directly into the skin [19]. L-carnitine, a drug used in mesotherapy, is FDAapproved, not recommended for those who are pregnant or nursing; not advised for those with impaired kidneys. It is naturally present in the body as a fat-burning component of metabolism [20]. Biotin is actually a type of B vitamin sometimes called vitamin H or B7. It is a water-soluble nutrient and even though it is usually left out of Nutrition Facts labels, it is essential for cell growth and metabolism of fats and amino acids. It is also sometimes used in mesotherapy, although it is not approved (not considered a food or a drug) [21]. Minoxidil is another drug FDA-approved for topical use. This drug is actually the generic name for Rogaine. The product used by men (and women) who are losing hair. It is part of a not-too common method of mesotherapy that involves injecting minoxidil into the scalp with a Skin & Scalp Roller (a medical instrument) to encourage hair growth [22]. Unlike many other drugs used in mesotherapy which are approved for oral consumption, retinoic acid has FDA-approval for topical treatment. It is widely used in beauty products because it has been proven to be an effective tool against numerous skin problems, from acne to wrinkles. A similar compound, alpha lipoic acid is also approved for topical use; however the FDA has warned that it often leads to increased sensitivity of the skin to the sun. Phosphatydlcholine is one drug used in mesotherapy that the FDA actively lobbies against, because it is a drug that the FDA is able to regulate and is not approved by the administration for any sort of use. Despite this, it is still a very popular component in many mesotherapy kits, sold under the name Lipostabil. It is also commonly abbreviated as PC or PPC. ASPS Guiding Principles for Mesotherapy The terms "mesotherapy" and "injection lipolysis" are often used interchangeably. While somewhat different, both therapies are advertised as a non-surgical alternative to liposuction. As the promotion and popularity of mesotherapy and injection lipolysis has increased, so too has the controversy surrounding their use. Questions regarding the safety and efficacy of these therapies and whether or not their use is in violation of federal or state regulations abound. Before pursuing mesotherapy or injection lipolysis use in a practice, plastic surgeons should be aware of, and carefully consider, the numerous medico-legal aspects associated with these therapies. 1. Background Originally developed in Europe, mesotherapy is a general term describing a technique that utilizes a series of injections of pharmaceutical and homeopathic pg. 24 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. medications, plant extracts, vitamins, and other ingredients into subcutaneous fat. While mesotherapy has been touted for the treatment of a wide variety of ailments, one of its notable indications is for dissolving localized fat accumulations. The term injection lipolysis is used specifically in reference to the practice of injecting various phosphatidylcholinedeoxycholate formulations into subcutaneous fat deposits. The injections are generally administered over multiple treatment sessions. There are no standard formulations for either mesotherapy or injection lipolysis. 2. Regulatory Environment Food and Drug Administration (FDA) Approval:Currently, there is no known PDA-approved injectible solution or pharmaceutical preparation for mesotherapy or injection lipolysis. Thus, physicians who wish to perform this therapy for adipose reduction may be subject to some degree of liability as the FDA may review individual occurrences on a case-by-case basis for enforcement action. Compounding:The FDA regulates drugs bought and sold in the United States as well as establishes protocols for compounding drugs, the process of mixing drugs by a pharmacist or physician to meet the unique needs of a patient. Phosphatidylcholine and sodium deoxycholate are both FDA approved for uses other than mesotherapy or injection lipolysis. However, the legality of compounding them for the purpose of injection lipolysis is controversial, because combining phosphatidylcholine and sodium deoxycholate would produce a "new drug" that is not approved by the PDA for subcutaneous injections. As part of a statement issued February 1, 2008, the PDA clearly stated that most compounded drugs are not PDA-approved drugs. 1 Physicians pursuing this compounding approach to administer injection lipolysis may be subject to enforcement actions by the PDA if their practices do not meet the criteria outlined in the PDA Compounding Compliance Policy Guide.2 In addition, medical providers and pharmacists are bound to adhere to State regulations governing compounding, which are determined by individual state regulatory bodies. Off-label Use:Compounded drugs should not be confused with the "off-label" use of drugs. PDA approval of a drug indicates use of the drug for a specific purpose. Once a drug is approved by the PDA, a licensed physician may prescribe a drug for uses other than the indicated purpose, provided there is scientific evidence / literature to support such use. However, because the mixture of drugs and other ingredients in mesotherapy formulations produce a new drug that is not PDA approved for any purpose, its use would not be considered "off-label" use. State Regulation:The PDA shares regulatory authority over the use of drugs with individual states. Both Kansas and Nebraska have taken steps to limit the utilization of mesotherapy by physicians. On March 12, 2008, the Kansas Board of Healing Arts voted to prohibit use of phosphatidylcholine and/or sodium deoxycholate unless part of an PDA-sanctioned clinical trial or an individualized prescription from a compounding pharmacy for a specific patient. The ban also prohibits bulk purchases of the products. On February 19, 2008, the Nebraska Legislature introduced a bill that prohibits the administration of subcutaneous injection of phosphatidylcholine or sodium deoxycholate, or any combination of the substances for the purpose of eliminating or reducing local fat accumulation. Upon its recess in April 2008, the Legislature indefinitely postponed the bill. 3. Scientific Evidence There is very limited scientific evidence available on mesotherapy or injection lipolysis for fat reduction. A thorough search of the literature found 14 references for mesotherapy for fat reduction or injection lipolysis. Based on a critical appraisal of the relevant literature, the majority of articles were found to be levels IV and V, the lowest levels of validity for scientific studies. Three of the fourteen articles were not rated due to the fact they were too poorly designed; and, were therefore rated to be of low quality. 3-15 Furthermore, these studies do not offer comparable information on formulations and dosages of key ingredients, which are two elements necessary to compare safety and efficacy of treatments. The low levels of validity and quality of the literature does not allow ASPS to support a recommendation for the use of mesotherapy/injection lipolysis for fat reduction [23]. 4. Guiding Principles It is the individual physician's responsibility to understand and abide by all applicable Federal, State, and local regulations. Only PDA-approved uses of drugs may be commercially advertised; it is illegal to commercially advertise any non-approved or off-label use. Each physician must ensure that a means for providing the appropriate informed consent for each patient has been established prior to the treatment. The consent should include the fact that there is very limited scientific evidence available to verify the efficacy of mesotherapy and/or injection lipolysis for the treatment of dissolving fat accumulations. Because safety and efficacy cannot be ascertained from the available body of English literature, ASPS pg. 25 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. believes further scientific testing of fat reduction mixtures is needed before recommendations on their use may be formally issued. Physicians administering mesotherapy treatments should be aware of the chemicals/drugs being injected, dosages, particular side effects, and potential interactions. Records of injected substances and dosages administered should be available in the patient's medical record and accessible to other treating physicians. When interpreting and applying these guiding principles to their individual practice, physicians should use their personal and professional judgment. These guiding principles should not be construed as a rule and are not meant to serve as the standard of medical care. Common Complicationsand Adverse Reactions in a Mesotherapy Practice Mesotherapy complications may be broken down into 3 categories: untoward reactions to pharmaceuticals, pigmentation problems, and necrosis Allergic reactions to biologicals are seen fairly often. The enzymes hyaluronidase, collagenase, and phosphatidylcholine are the only drugs causing allergic reactions that we have seen. Hyaluronidase can create a wheal and flare reaction of the immediate or delayed hypersensitivity type. In the immediate type, the reaction is seen within 15 minutes and consists of a raised, erythematous wheal that is intensely pruritic. A skin test will reveal this immediate hypersensitivity reaction before the patient undergoes a treatment containing hyaluronic acid. The delayed hypersensitivity reaction to hyaluronidase has the same appearance but may not reveal itself until after multiple treatments. As many Hymenoptera contain hyaluronidase in their venom, an allergy to these insects should alert the mesotherapist to the likelihood of a wheal and flare reaction occurring when this ingredient is used. Collagenase hypersensitivity may also be seen either in the immediate post-treatment period or as a delayed reaction. It presents as a series of raised patches that are tender to the patient but not pruritic. Phosphatidylcholine allergy is much less likely but has been seen after an initial treatment. It appears as a fine, pruritic, maculopapular rash distant from the treated area. In all these allergic instances the reaction responds to parenteral or oral diphenhydramine in dosages of 25-50 mg. A protocol we have used is 25 mg of diphenhydramine every 6 hours for 2 days along with 30 mg of prednisone initially, followed by 5 mg of prednisone every 6 hours also for 2 days. When a patient has an allergy to hyaluronidase, collagenase, or phosphatidylcholine, pretreatment beginning the day before mesotherapy with 5 mg of prednisone followed by 10 mg of prednisone on the day of the treatment has prevented or severely reduced the reactions. Occasionally, in a patient pretreated with corticosteroids, diphenhydramine will also be required following treatments if there is continued pruritus. Aminophylline is commonly used in adiposesculpting mesotherapy formulae. This drug has a narrow therapeutic index with problems encountered at dosages around 250 mg in most patients. Nausea, vomiting and diarrhea are the most common complaints with onset occurring 4 to 8 hours postprocedure.3 When serum levels increase to greater than 20 mg/mL cardiac arrhythmias and seizures are possible.3 Repeated dosages of aminophylline may also decrease serum potassium over time.3 In patients with risk factors for potassium wasting, this electrolyte should be monitored, and any patient experiencing muscle cramping should have this electrolyte assayed immediately. Some mesotherapists will administer a preprocedure parenteral anti-emetic in select patient populations. Hyperpigmentation problems status postmesotherapy procedures have also been noted. In the highmelanin Fitzgerald skin types V and VI, postinflammatory hyperpigmentation has occurred. Topical preparations containing, singly or in combination, kojic acid, hydroquinone and/or glycolic acid have been helpful in resolving this unfortunate complication over months. Of greater concern, and which may occur irrespective of Fitzgerald skin type, is urticariapigmentosa. We have seen this only following wheal and flare reactions in the skin. In the resolution of the wheal, a purplish to brownish discoloration appears in the subcutis and remains for months despite all efforts to eradicate it. Over time these have gradually improved, but we have found no way to hasten their resolution. Hyperpigmentation of any type is not common in our practice, the incidence being 0.87%. Nonetheless, pigmentation problems, although not serious, can be very distressing to patients. In summary, hypersensitivity reactions are common and easily managed. Adverse drug reactions, although not frequent, may also be anticipated or treated with common-sense protocols. Hyperpigmentation complications are not medically serious, but many patients become concerned when these develop and wish to discontinue treatment. Tissue necrosis is rare, but serious. With attention to appropriate drug selection and delivery protocols, mesotherapists are unlikely to encounter this situation [24]. Dangers of Mesotherapy If you're desperate to lose fat from one stubborn area, or if you're tired of trying to hide your cellulite, mesotherapy may seem like the answer. Many people claim it's a miracle cure for fat. However, you should be wary of so-called miracles. Mesotherapy is unregulated, and the American Society of Plastic Surgeons warns that it could be dangerous. pg. 26 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. 1. Identification Mesotherapy is a nonsurgical treatment to remove fat. Proponents call it an alternative to liposuction. Mesotherapy treatments begin by discussing your goals with your doctor. He then creates an individualized mixture of medicines and plant extracts to inject into the layer of fat tissue during your mesotherapy sessions. The mixture removes fat cells and evens out cellulite. You'll receive between three and 15 sessions of mesotherapy, given every other week, before your treatment is done. 2. Benefits Those who support mesotherapy claim it is both safer and cheaper than liposuction, which is currently the only other medical method to remove fat cells from the body. It can be done in a doctor's office, and the recovery time is shorter. It also provides help for those whose weight problem isn't bad enough to be eligible for liposuction. Mesotherapy reduces cellulite as well, while liposuction doesn't. 3. Side Effects The most prominent side effect of mesotherapy is swelling and bruising around the area of the injections. In most cases, this goes away within a week or so. Some people have allergic reactions to the medications used, either immediately or later. You may see skin discoloration or a rash. Mesotherapy can also cause infection. 4. Dangers Mesotherapy is not regulated by the U.S. Food and Drug Administration, and the FDA has not approved many of the drugs used in the procedure. A different combination of drugs is used for each patient, so it can be difficult to test the treatment's efficacy. The Device and Technique Assessment Committee of the American Society of Plastic Surgeons warns patients to be cautious about mesotherapy until more testing can be done. No one is sure what happens to the fat cells after they are removed, and no one is sure what effect the mesotherapy drugs have on the rest of the body's systems. Mesotherapy methods are not standardized, and long-term effects haven't been studied [20,24]. Fig1.Mesotherapy - Face after treatments Fig 2.Mesotherapy – Targeted fat cells pg. 27 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. Table 1. Mesotherapy and LipoDissolve Ultra Treatments Mesotherapy/ LipoDissolve Ultra is a non-surgical treatment to help dissolve unwanted areas of fat tissue ... similar to liposuction but without the surgery and downtime. LipoDissolve Ultra can effectively treat areas such as the flanks (love handles), the lower tummy "pouch" just below the belly button, upper hips, and upper outer thighs (saddle bags), upper arms, double chins and jowls. Pre-treating the area with an ultra-sound massage increases the fat cells' receptivity to the LipoDissolve Ultra treatment solution. When micro injections of the mesotherapy-LipoDissolve Ultra solution is administered into the targeted area, the solution is quickly absorbed into the fat cells. Immediately after treatment, the target areas are once again treated with ultrasonic massage for increased comfort, to aid in even distribution of solution and to minimize post treatment edema. Within the target areas, the treatment causes fat cells to dissolve. The dissolution products of the fat cells are removed in a natural manner, similar to the way blood is removed within a bruise. Inflammation of the overlying skin causes the skin to retract, tighten and become smooth. Fat cells that are dissolved by the process are permanently lost. pg. 28 Latha P. and Vandana K.R. / International Journal of Advanced Pharmaceutics / 1 (1), 2011, 19-29. CONCLUSION Mesotherapy proponents base their claims that mesotherapy is safer than liposuction on the fact that mesotherapy is a nonsurgical procedure. However, liposuction is FDA-approved and -regulated, while many uncertainties surround mesotherapy. Proponents' claims that mesotherapy is cheaper than liposuction aren't necessarily true, either. Mesotherapy costs between $1,000 and $1,500 per session; depending on how many sessions you need, that can quickly add up to the cost of surgery. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Adelson H. 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