Surgical remodeling of the silhouette by aspiration lipolysis or selective lipectomy

The author, a pioneer in originating the technique of suction lipectomy, discusses in detail the pathophysiology of the fat cell and fat metabolism. In addition, he describes the surgical means by which, since 1977, he has popularized this innovative new approach to the treatment of unsightly fat deposits in many sites in the body, including the thighs, buttocks, abdomen, hips, arms, ankles, breasts, and submental regions.     

Beta-blockade and lipolysis during endurance exercise

Summary Inhibition of adipose tissue lipolysis may be involved in the impairment of endurance capacity after administration of a -adrenoceptor blocker. During endurance exercise, no significant decrease in plasma glycerol and free fatty acid (NEFA) concentrations after -adrenoceptor blockade is found. However, the levels during recovery from exhaustion are lower after -adrenoceptor blockade. This study was designed to investigate whether the lower levels after exercise are due to -adrenoceptor blockade or to the shorter time to exhaustion after administration of a -adrenoceptor blocker.In a single-blind study, 11 well-trained male subjects (age 23 (0.9) y) performed a cycle ergometer test at 70% W_max until exhaustion 2 h after intake of 80 mg propranolol. One week later, the test was repeated after intake of placebo and was stopped at the time of exhaustion in the previous test. Average exercise time was 24 min. During exercise plasma glucose was lower, whereas plasma lactate and the respiratory exchange ratio were significantly higher when the subjects were on propranolol. Glycerol and NEFA concentrations during exercise were not significantly different between the two conditions. Despite an identical exercise time, glycerol and NEFA concentrations during recovery were significantly lower after propranol treatment.In conclusion, lipolysis is inhibited during exercise after propranolol, probably causing a shift from fat to carbohydrate combustion.     

H3 receptor-mediated inhibition of noradrenaline release: an investigation into the involvement of Ca2+ and K+ ions,G protein and adenylate cyclase

The effects of ₂-adrenoceptor agonists (dexmedetomidine, oxymetazoline), alone or in combination with various -adrenoceptor subtype-selective antagonists (CH-38083, idazoxan, WB4101, BRL44408, ARC-239, prazosin), on noradrenaline- and isoprenaline-induced lipolysis were investigated in human isolated abdominal subcutaneous fat cells. The rank order of potency of antagonists in preventing dexmedetomidine- and oxymetazoline-evoked suppression of isoprenaline-induced lipolysis was (pA₂-values): CH-38083 (7.69 and 7.48) idazoxan (7.5 and 7.41) > BRL 44408 (7.23 and 7.19) WB 4101 (7.13 and 7.12) > prazosin (5.18 and 5.17) > ARC-239 (4.72, 4.9). While CH-38083 and idazoxan, non-subtype selective ₂-adrenoceptor antagonists and BRL44408, a selective a_2A-adrenoceptor antagonist as well as WB4101 potentiated the lipolytic effect of noradrenaline, ARC-239, the selective _2B-adrenoceptor antagonist failed to affect it. In addition since the _2A-adrenoceptor selective agonist, oxymetazoline concentration dependently inhibited the lipolytic effect of isoprenaline, and WB4101 and BRL44408 (a_2A-adrenoceptor antagonists) antagonised the effect of oxymetazoline in a competitive manner, it is concluded that the a_2A-adrenoceptor subtype is involved in antilipolysis. In addition, functional evidence was obtained that there is an interaction between _2A- and -adrenoceptors located on the cell surface of adipocytes, through which locally released noradrenaline and/or circulating circulating adrenaline influence lipolysis.On leave from Institute of Medical Pharmacology, University of Pisa, Via Roma 55, I-5626 Pisa, Italy Correspondence to: E. S. Vizi at the above address     

Studies on metabolic actions of some xanthine derivatives of dopamine in the rat

Summary The lipolytic and hyperglycaemic actions of three xanthine derivatives of dopamine were studied in fed rats by determining the plasma levels of glycerol, free fatty acids and glucose. All three derivatives, 7-propyl-theophylline-dopamine, 7-(3-methyl)-propyl-theophylline-dopamine and 7-(2-methyl)-propyl-theophilline-dopamine, had a longer duration of action on lipolysis than had dopamine. These xanthine derivatives stimulated lipolysis at 10-to 100-times lower doses than dopamine and also had a greater maximal effect. Glycogenolysis was stimulated by 7-(3-methyl)- and 7-(2-methyl)-propyl-theophyllinedopamine at lower doses than by dopamine, the maximal effect, however, being smaller than that of dopamine. 7-propyl-theophylline-dopamine had practically no hyperglycaemic effect. Pretreatment with the -adrenoceptor blocking agents, phentolamine and dihydroergotamine, blocked the increase of the plasma level of glucose induced by dopamine, whereas the hyperglycaemic effect of 7-(3-methyl)-propyl-theophylline-dopamine was better antagonized by the -adrenoceptor blocking agent, propranolol. The -adrenoceptor antagonists had no clearcut effects on the lipolytic action of dopamine or its xanthine derivatives, which was, however, clearly antagonized by pretreatment with propranolol. Desipramine and reserpine, at doses which prevented the metabolic actions of tyramine, partially blocked the lipolytic and hyperglycaemic effect of dopamine, but not those of the xanthine derivatives. This suggests that the xanthine derivatives- in contrast to dopamine- do not have an indirect, tyramine-like component in their metabolic actions. Pretreatment with pargyline, an inhibitor of monoamine oxidase, strongly enhanced the metabolic effects of dopamine, but to a lesser extent the actions of its xanthine derivatives, indicating that these derivatives are more resistant to monoamine oxidase than is dopamine. The results indicate that the xanthine derivatives have metabolic effects similar to those of dopamine, but differ from dopamine in their activity and relative affinity with respect to metabolic - and -adrenoceptors and in their mechanism of action as well as in their metabolism.Deceased August 6, 1978     

Methylamine but not mafenide mimics insulin-like activity of the semicarbazide-sensitive amine oxidase-substrate benzylamine on glucose tolerance and on human adipocyte metabolism

It has been reported that benzylamine reduces blood glucose in rabbits, stimulates hexose uptake, and inhibits lipolysis in mouse, rabbit, and human adipocytes. In the presence of vanadate, benzylamine is also able to improve glucose disposal in normoglycaemic and diabetic rats. Such insulin-mimicking properties are the consequence of hydrogen peroxide production during benzylamine oxidation by semicarbazide-sensitive amine oxidase (SSAO). The aim of the study was to determine whether other SSAO-substrates could share such potential antidiabetic properties. Thus, mafenide, a synthetic antimicrobial sulfonamide structurally related to benzylamine, and which has been recently reported to interact with SSAO, was tested in the above mentioned models, in parallel with methylamine, a proposed endogenous SSAO-substrate. All tested amines stimulated glucose uptake and inhibited lipolysis in rat and mouse fat cells. Methylamine and benzylamine, but not mafenide, reduced the hyperglycaemic response during a glucose tolerance test in rabbits while the three amines tested were devoid of insulin-releasing activity under both in vivo and in vitro conditions. In human adipocytes, mafenide did not stimulate glucose transport since it was not a high-affinity substrate for SSAO and generated less hydrogen peroxide than benzylamine or methylamine. Therefore, mafenide could not be considered as an antidiabetic drug despite being oxidized and exhibiting insulin-mimicking effects in rat and mouse adipocytes. By contrast, the endogenous substrate methylamine improved glucose utilization in all in vitro and in vivo models, leading to consider novel SSAO substrates as drugs with potential anti-hyperglycaemic properties.     

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.     

α2-Heremans–Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action

Aims/hypothesis The aim of this study was to investigate the effect of single-nucleotide polymorphisms (SNPs) in the gene encoding the human ₂-Heremans–Schmid glycoprotein (AHSG) on obesity and insulin action in adipocytes.Methods We screened 24 individuals for SNPs in AHSG. Six haplotype-tagging SNPs were genotyped in 188 lean and 176 obese otherwise healthy women for whom common blood chemistry phenotypes were also available. Adipocyte lipolysis and lipogenesis phenotypes were quantified in a subset of 117 lean and 174 obese women.Results The –469T>G SNP, which is located in the 5 region of AHSG, was associated with insulin-mediated inhibition of lipolysis and stimulation of lipogenesis, as well as basal and 8-bromocyclic AMP-stimulated lipolysis. Three AHSG SNPs were associated with circulating levels of cholesterol. None of the six genotyped SNPs or inferred haplotypes were associated with BMI, calculated percent body fat, waist circumference, circulating levels of glucose or insulin, or homeostasis model assessment of insulin resistance, which was used as an estimate of in vivo insulin sensitivity.Conclusions/interpretation Our results are in agreement with a threshold model of susceptibility for insulin resistance and type 2 diabetes, in which specific genetic loci regulate intermediate molecular phenotypes. When an individuals set of susceptibility alleles at such loci exceeds a threshold, clinical disease occurs. Lipolysis in adipocytes appears to be a phenotype that is particularly sensitive to variation in AHSG.     

Obésité et diabète. Les variations des acides gras libres circulants sous charge orale en glucose

Résumé L'étude des variations des acides gras libres (AGL) du plasma est entreprise chez 58 sujets obèses et 18 sujets normaux témoins, mis dans des conditions d'exploration identiques. On constate chez les sujets obèses un comportement global des AGL qui est différent de celui des sujets normaux témoins dans la mesure où la dépression initiale de leur taux est plus lente et le maximum de chute est différé aux temps tardifs de l'épreuve. Il en résulte une tendance globale à une absence de réascension secondaire du taux des AGL circulants, à l'inverse de ce qui succède chez le sujet normal, où la valeur moyenne des AGL à la 4^ème h de l'épreuve est plus élevée que le taux moyen de base. Tant chez le sujet normal que chez le sujet obèse, on constate d'importantes variations individuelles. Les anomalies rencontrées chez les obèses sont d'autant plus évidentes que la tolérance glucidique se rapproche des conditions du diabète; cela laisse à penser qu'il existe, chez ces sujets, des relations étroites entre la dégradation de la tolérance glucidique et les anomalies du comportement des AGL circulants. Ce dernier problème est discuté en fonction des relations entre l'obésité et la maladie diabétique.

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Summary The variations of plasma non-esterified fatty acids (NEFA) in 58 obese subjects and 18 normal controls have been studied in identical conditions of investigation. The overall behavior of NEFA in the obese differed from that in the controls in that the initial fall was slower and the maximum depression occurred late in the test. Hence the overall tendency was for the secondary rise in the NEFA level to be missing, which was the reverse of what happened in the normals, in whom the mean NEFA value at the 4th h was above the starting value. Both in normals and in obese subjects there was a considerable individual variation. The anomalies in the obese became more marked as carbohydrate tolerance approached diabetic level; this suggests that there is in these subjects a close connexion between the decline of carbohydrate tolerance and the anomalies of plasma NEFA behavior. The latter is discussed in terms of the relationships between obesity and diabetes.

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Zusammenfassung Bei 58 Fettsüchtigen und 18 Normalpersonen wurden unter identischen Versuchsbedingungen die Variationen der freien Fettsäuren des Plasma (FFA) verfolgt. Bei Fettsüchtigen wurde ein von den Normalpersonen verschiedenes Gesamtverhalten der FFA festgestellt; der Unterschied ist umso grösser je langsamer die anfängliche Senkung des FFA-Spiegels bei den Fettsüchtigen erfolgt und je mehr das Maximum der Abnahme verzögert ist. Daraus ergibt sich eine Gesamttendenz zum Fehlen des sekundären Anstiegs des zirkulierenden FFA-Spiegels, im Gegensatz zu den Verhältnissen bei Normalpersonen, wo der Mittelwert der FFA in der 4. Stunde der Probe höher ist als der mittlere Ausgangswert. Sowohl bei Normalpersonen als auch bei Fettsüchtigen werden erhebliche individuelle Unterschiede beobachtet. Die bei Fettsüchtigen beobachteten Anomalien sind umso ausgesprochener je mehr sich ihre Kohlehydrattoleranz einer diabetischen Stoffwechsellage nähert; das lässt den Verdacht aufkommen, dass bei diesen Individuen eine enge Beziehung zwischen der verminderten Glukosetoleranz und dem abnormen Verhalten der zirkulierenden FFA besteht. Dieses Problem wird im Hinblick auf die Beziehungen zwischen Fettsucht und Diabetes mellitus besprochen.

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Resumen Se emprendió el estudio de las variaciones de los ácidos grasos libres (AGL) del plasma en 58 individuos obesos y 18 testigos normales, puestos en idénticas condiciones de exploración Se constata que en los sujetos obesos un comportamiento global de los AGL es diferente al de los individuos testigos normales en la medida o la depresión de su porcentaje es más lento y el máximo de caída se difiere a los tiempos tardíos de la prueba. Resulta una tendencia global a una ausencia de reascensión secundaria del porcentaje de los AGL circulantes, al contrario de lo que sucede en el individuo normal, en el que el valor medio de los AGL a las cuatro horas de la prueba es más elevado que el porcentaje medio de base. Tanto en el sujeto normal como en el sujeto obeso, se comprueban importantes variaciones individuales. Las anomalías encontradas en los obesos son mucho más evidentes cuando la tolerancia se acerca a las condiciones de la diabetes; esto lleva a pensar que existe, en estos individuos, estrechas relaciones entre la degradación y la tolerancia glucídica y las anomalias del comportamiento de los AGL circulantes. Este último problema se discute en función de las relaciones entre la obesidad y la enfermedad diabética.

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Riassunto Le variazioni dei NEFA plasmatici sono state studiate in 58 pazienti obesi e in 18 individui normali di controllo, posti in condizioni sperimentali identiche. Nei soggetti obesi è stato osservato un comportamento globale dei NEFA diverso da quello degli individui normali di controllo, nel senso che la depressione iniziale è più lenta e la massima caduta si verifica nelle fasi tardive della prova. Ne risulta una tendenza globale all'assenza di risalita secondaria dei NEFA circolanti, contrariamente a quanto avviene nel soggetto normale, in cui il valore medio dei NEFA alla 4^a ora del test è più elevato rispetto al livello medio di base. Sia nel soggetto normale che nell'obeso, si riscontrano importanti variazioni individuali. Le anomalie rilevate negli obesi sono tanto più evidenti quanto più la tolleranza al glucosio si avvicina alle condizioni esistenti nel diabete: ciò induce a ritenere che in questi soggetti esistano stretti rapporti tra la diminuzione della tolleranza al glucosio e le anomalie del comportamento dei NEFA circolanti. Quest'ultimo problema viene discusso alla luce delle relazioni tra obesità e malattia diabetica.

     

Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.KEY WORDS: Pharmacokinetics, Lipolysis, IVIVC, Efflux transporters, Lymphatic delivery, Food effectAbbreviations: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; C_max, maximum plasma concentration; CMC, critical micellar concentration; CYP, cytochrome; DDS, drug delivery systems; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; GIT, gastrointestinal tract; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; log P, n-octanol/water partition coefficient; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E