Some studies he reported that the topical forms with aminophylline as the active ingredient appear to be relatively effective on local fat burning while hing no/minimal side effects. This systematic review accumulates all of the data on the local fat-burning potency of aminophylline topical formulation.
MethodsDocuments were retrieved from PubMed, Web of Science, and Scopus databases until Aug 2022. Data were extracted from clinical trials reporting the reduction in thigh or waist circumference as a result of using topical forms containing aminophylline. Screening of included studies was performed independently by two authors and the quality assessment of included studies was performed based on the Cochrane Collaboration’s approach.
ResultsOf the 802 initial studies, 5 studies were included in the systematic review. Several concentrations of aminophylline were used in different studies. Most studies administred the topical formulation on participants’ one thigh, and the other thigh was considered to be the control for comparing the fat reduction amount. Except for one study, all other studies reported that all participants lost more fat on the treated area than the control groups. The amount of fat reduction differed in studies regarding their different aminophylline concentrations and administration routines. In the case of side effects, except for some studies reporting skin rashes, other studies reported no significant side effects at all.
ConclusionsAminophylline topical formulation offers a safe, effective, and much less invasive alternative to cosmetic surgery for localized fat reduction. It seems that the 0.5% concentration, administered five times a week for five weeks is the most potent concentration. However, more high-quality clinical trials are needed to verify this conclusion.
Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022353578.
Keywords: aminophylline, topical, fat reduction, thigh, lipolysis
IntroductionObesity is a multifactorial chronic and progressive disease of excess adipose tissue that can occur at any age (1). According to reports (2), 46% of adults aged ≥20 are overweight or obese worldwide. Moreover, United States (US) has the highest obesity rate, with a prevalence of 34% in adults (3). Studies he also predicted that nearly 1.92 billion people worldwide will be obese or overweight by 2030 (2). On top of the physical health risks associated with obesity, negative psychological consequences are also inevitable. Depression (4–6), body image dissatisfaction (7), and stress (7–9) are all examples of this regard that can reduce one’s quality of life both directly and indirectly.
Regarding obesity management strategies, behioral modification is one of the main approaches. However, depressed mood and anxiety reduce obese people’s functioning and their adherence to lifestyle changes (8). Medical interventions, on the other hand, are becoming more popular, and the obesity control guidelines strongly recommend medical interventions for overweight patients (10). In the case of these interventions, the most common approaches are oral/injectable anti-obesity medications (11–13) and bariatric surgeries (14). However, there are some drawbacks to these medical interventions too. The most significant disadvantages of oral anti-obesity agents (i.e., phentermine/topiramate, naltrexone/bupropion, and orlistat) are their systematic side effects, such as neuro-psychiatric, fetal, and cardiovascular side effects (11–13). Furthermore, it has been reported that the degree of weight loss provided by anti-obesity medications does not typically provide the type of cosmetic benefit that many patients seek (11, 12). In the case of injectable medications (i.e., liraglutide) and bariatric surgeries, their main disadvantage is their aggressive method of administration and their high costs (12, 14, 15). As a result, the most appropriate drug is one that is more effective, has fewer side effects, is less expensive, and is administered in a non-aggressive manner.
Topical formulations, on the other hand, are non-aggressive methods of drug administration and he significantly fewer side effects due to their low systematic absorbance. Regarding efficacy, several attempts he been made to develop a topical formulation for local fat loss (16–21). Among all, some studies he reported that the topical forms with aminophylline as the active ingredient appear to be relatively effective on local fat burning while hing no/minimal side effects.
Therefore, the goal of this study was to accumulate all of the data on the local fat-burning potency of aminophylline topical formulation in order to get one step closer to developing topical and effective fat burner agents.
MethodsPrior to the start of the study, a detailed research protocol was prepared and registered in the international prospective register of systematic reviews (PROSPERO) with the CRD42022353578 ID, which was then followed throughout the process. The 27-item PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement was used as the reporting model for this systematic review to ensure inclusiveness (22). Furthermore, the 12-item “PRISMA for abstract” extension was used to write the abstract (23).
Search strategyA complete search strategy used for each database is reported in Supplementary Table 1 . Two researchers independently searched until Aug 2022 for relevant articles published (with no restriction of publication year) in the following data sources: PubMed, web of science, and Scopus using the following search terms: “Aminophylline” OR “Theophylline ethylenediamine” OR “Theophylline-ethylenediamine” AND “Topical” OR “Topical administration” OR “Cream” OR “Lotion” OR “Local” OR “Subcutaneous” OR “Fat” OR “Fat burn” OR “Fat burner” OR “Fat burning” OR “Fat reduction” OR “Fat reducer” OR “Fat loss” OR “Lipolysis” OR “Contouring” OR “Body contouring” OR “Waist” OR “Thigh” OR “Skin” OR “Circumference” OR “Regional” OR “Cellulite” OR “Adipose tissue” OR “Adiposity” OR “Obesity” OR “Mesotherapy” OR “Cosmetic”. Studies with any search terms in their title or abstract were found, and their abstracts were pooled and imported into Endnote Reference Manager. After excluding duplicate studies and completing screening stages, the research team decided which studies will finally be chosen.
Eligibility criteria and study selectionObesity and cellulite were designated as the study’s exposures of interest. The intervention was defined as topical aminophylline application, and the local fat reduction in the studied body area, as our primary outcome of interest, was compared between exposed and unexposed populations. After excluding duplicate studies, two independent researchers performed the first screening stage, examining the remaining articles in accordance with the study’s stated objectives. Reviews, animal studies, experimental studies, clinical trials, and editorial or other types of letters were excluded at this stage.
Through the second screening stage, clinical trials were included if:
Aminophylline was used in topical form (cream, lotion, ointment, and gel) alone or in combination with other ingredients.
Desired information on the participants was provided.
Results were reported as the amount of subcutaneous fat reduced.
Studies got excluded if:
The study was on the production process of topical formulation.
Fat reduction was not reported at all or as a result of using topical aminophylline.
Each researcher reported the studies they had picked after the second screening stage, and the team decided which studies would ultimately be selected for data synthesis. Disagreements were settled, if necessary, by a discussion with a third research team member.
Data extractionData from papers were individually gathered by two reviewers and entered into Microsoft Excel.
The data that was extracted included:
Publication details: author(s), title, journal, date, stated aims.
Study characteristics: study location, number of participants, participants’ characteristics, pharmaceutical form of aminophylline, other ingredients of topical formulation (if applicable), and body area(s) studied.
Critical data: Topical formulation and concentration of active pharmaceuticals, administration routine, other interventions (if applicable), adverse effects (if reported), and final results in as much detail as possible (mean ± SD or median ± SE).
Risk of bias assessmentUsing the Cochrane Collaboration’s approach (24), two reviewers independently categorized studies as hing a low, high, or uncertain risk of bias in various domains. Then, if necessary, disagreements were discussed with a third researcher on the research team in order to be resolved.
The risk assessment method developed by Cochrane Collaboration evaluates the probability of bias in six areas for each study. Areas are “Selection bias”, “Performance bias”, “Detection bias”, “Attrition bias “, “Reporting bias”, and “Other bias”. The “selection bias” section checks whether the study clearly describes the allocation sequence generation process so that it can be determined whether or not it should result in comparable groupings. Furthermore, it also verifies whether the study has indicated if intervention allocations could he been anticipated before or during enrollment by providing enough information about the technique employed to disguise the allocation sequence. The “Performance bias” section monitors if the study describes the procedures taken, if any, to prevent trial participants’ intervention status from being known to researchers. The “Detection bias” section ensures if the study describes all procedures taken, if any, to prevent participants’ particular interventions from being known during outcome evaluation. The “Attrition bias” determines whether the study describes how comprehensive the outcome data is for each primary outcome, taking attrition and analytical exclusions into account. And finally, the “Reporting bias” section examines if the study describes the methodology used to analyze selective outcome reporting.
Results Study selectionFigure 1 displays a flowchart of the study selection process’ summary. Using the aforementioned search protocol, 802 articles were initially found, including 299 from PubMed, 321 from Scopus, and 182 from Web of Science. The total number of 399 items made it to the first stage of screening after 403 duplicates were eliminated. Then, 382 articles were excluded as a consequence of the first step’s title and abstract screening because they were either unrelated to the issue or did not include the information that was sought. Twelve studies were eliminated from the 17 remaining papers that underwent full-text screening because there was insufficient information presented on the relationship between the topical use of aminophylline and local fat reduction. Finally, data from five papers (17, 18, 25–27) were used after they satisfied all inclusion criteria.
Figure 1.
A summary of the study screening process.
Basic characteristics of the selected studiesTable 1 shows the basic characteristics of the five studies that were finally included. All studies except one that was carried out in England (25), were done in the US. Six sub-trials were included in one of the studies (18), of which five were utilized in this study. That one study was dropped because it utilized injection administration. In general, sample sizes in studies were small but varied, ranging from five to 25 participants and totaling 117 people, which were mostly women. The majority of the research was done on participants who were obese, thought they were obese, or thought their thighs were unattractively fat. With the exception of two studies that created lotion (27) and gel (17) forms, all other studies formulated creams and ointments. Three of the trials added additional components to the formulation. Forskolin, yohimbine, caffeine, L-carnitine, and gotu kola (Centella asiatica) were added in two of the studies to boost the fat-burning impact, while glycolic acid was added in the other to increase cream penetration into the skin. Three trials used the Aquaphor® base for formulating ointment. Regarding the body area(s) tested, all studies tested on the thighs, except for one study that tested the topical formulation on the waist (26). Among all, two studies examined the buttocks as well (17, 25).
Table 1.Basic characteristics of clinical trials evaluating the effect of topical aminophylline in local fat reduction.
Author, year Study location Number of participants Participants’ characteristics Pharmaceutical form Other ingredients Body area(s) studied Artz and Dinner (17) United States 12 volunteers – Gel – Lateral thighs and buttocks Greenway et al. (18)(Trial 2) United states 5 women Participants were more than 20% above their desirable weights. Ointment • Aquaphor® base• Forskolin• Yohimbine Thighs Greenway et al. (18)(Trial 3-3) United states 5 women Participants were greater than 20% overweight. Ointment Aquaphor® base Thighs Greenway et al. (18)(Trial 4) United states 23 women Participants were greater than 20% overweight. Ointment Aquaphor® base Thighs Greenway et al. (18)(Trial 5) United states 11 women • All participants felt that their thighs were undesirably fat.• Some women wanted to lose weight while others were satisfied with their present weight. Cream – Thighs Greenway et al. (18)(Trial 6) United states 12 women • All participants felt that their thighs were undesirably fat.• Some women wanted to lose weight while others were satisfied with their present weight. Cream – Thighs Collis et al. (25) England 17 women Participants were over 18 years old with cellulite of the thighs and buttocks. Cream 10% glycolic acid Thighs and buttocks Caruso et al., (26) United states 25 men and women • All participants were obese and overweight with a BMI greater than 27 kg/m2.• Participants’ age was between 21 and 65 years.• Participants had android fat distribution (characterized by a waist to hip ratio >0.80 in women or >1.0 in men). Cream – Waist Escalante et al. (27) United states 7 women – Lotion • Caffeine,• Yohimbe• L-Carnitine• Gotu kola Thighs Open in a new tabOutcomesA detailed summary of studies evaluating the effect of topical aminophylline in local fat reduction is provided in Table 2 . As can be seen, several concentrations of aminophylline were used in different studies. Among all, the highest concentration of aminophylline used was 10%, with the administration of five times a week on participants’ one thigh (18). The other thigh was considered to be the control for comparing the fat reduction amount. Although participants were suggested to stick to a 900 to 1,100 kcal/day diet, they were not suggested to do any exercises. After six weeks, there had been a higher loss in participants’ thigh girth in the treated thigh than in the control thigh, with a mean ± SEM difference of 0.77 ± 0.66 cm for the lower girth and 0.78 ± 0.89 cm for the upper girth (p < 0.001). Heart rate, blood pressure, and blood chemistry all remained unchanged. Additionally, no theophylline could ever be found in blood samples, and no allergic reactions were documented.
Table 2.A summary of studies evaluating the effect of topical aminophylline in local fat reduction.
Author, year Topical formulation Administration Other interventions Results Adverse effects Artz and Dinner (17) 2% aminophylline Twice a day for 12 weeks • Patients oided any medications affecting theophylline serum levels. The thigh circumference was decreased an erage of 0.5 cm, but with no weight reduction. • Total cholesterol, triglycerides, HDL, and LDL did not show any significant changes after three months.• Aminophylline serum levels did not raise. Greenway et al. (18)(Trial 2) 1.2×10-5 M forskolin + 2.5×10-4 M yohimbine + 1.3×10-2 M aminophylline Five times a week for four weeks • 600 kcal/day diet• Patients were encouraged to follow a walking program• To increase transcutaneous absorption, the thighs were wrapped in warm 600 to 900 mOsm/L magnesium sulphate solutions for 30 minutes before each of the ointment applications.• An occlusive plastic wrap was placed over the area to which the ointment was applied throughout the 4-week study period. All participants lost more girth on the treated thigh than the control thigh with a mean ± SEM difference of 2.03 ± 1.36 cm (p