What is Tesofensine?
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What is Tesofensine?
Tesofensine (TE) inhibits the presynaptic reuptake of the neurotransmitter’s noradrenaline, dopamine and serotonin. Other types of selective serotonin reuptake inhibitors are used to treat depression and eating disorders, but they have generally failed to produce sustained weight loss. Sibutramine, in addition to its effect on serotonin, also inhibits the reuptake of other monoamines and has been shown to enhance postprandial satiety, reduce total calorie intake and to diminish the decline in energy expenditure usually associated with a diet-induced negative energy balance.
Tesofensine (TE) was originally studied for its effect on Parkinson's and Alzheimer's. Unfortunately, its exploration for these indications were limited because the patients were starting to lose too much weight. Since then, tesofensine has been studied as a way to treat obesity via its ability to reduce appetite. TE indirectly stimulates the cholinergic system and showed to be more successful than average weight loss remedies .
Tesofensine increases near transmission of a reuptake inhibitor 3 monoaminergic neurotransmitters in the brain. These neurotransmitters are serotonin, norepinephrine, and dopamine which help regulate energy balance and are linked to obesity and depression. On average, according to research, its 6-month weight loss results from research trials resulted in a weight loss of around 25 pounds.
What have Research Studies Shown?
Scientific research has revealed that Tesofensine can do the following:
• Increase energy metabolism
• Suppress appetite
• Improve the quality of life
• Improve body composition
• Neuroprotective
• Improved levels of insulin sensitivity
• Anti-depressant effects
Tesofensine in Research (Expanded)
Weight Loss:
Being overweight and/or obesity are major risk factors for diseases such as type 2 diabetes, coronary heart disease, sleep apnea and certain cancers, extensive efforts have been made to improve their treatment and prevention. Unfortunately, with the exception of bariatric surgery, these treatments most often produce only a modest and transient weight.
Weight-loss drugs produce an additional mean weight loss of only 3–5 kg above that of diet and placebo over 6 months, thus more effective pharmacotherapy of obesity is needed. In several studies, researchers have assessed the efficacy and safety of tesofensine—an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin—in people with obesity.
Research Example #1:
“In one recent study, researchers undertook a phase II, randomized, double-blind, placebo-controlled trial in five Danish obesity management centers. After a 2 week run-in phase, 203 obese patients (body-mass index 30−≤40 kg/m2) were prescribed an energy restricted diet and randomly assigned with a list of randomization numbers to treatment with tesofensine 025 mg (n=52), 05 mg (n=50), or 10 mg (n=49), or placebo (n=52) once daily for 24 weeks. The primary outcome was percentage change in body weight. Analysis was by modified intention to treat (all randomized patients with measurement after at least one dose of study drug or placebo).
161 (79%) participants completed the study. After 24 weeks, the mean weight loss produced by diet and placebo was 20% (SE 060). Tesofensine 025 mg, 05 mg, and 10 mg and diet induced a mean weight loss of 45% (087), 92% (091), and 106% (084), respectively, greater than diet and placebo (p<00001).”
Research Example #2:
“Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity.
This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated.
Tesofensine treatment (2.0 mg/kg/day for 14 days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis.
While acute administration of tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. See Figure 1 below.
Figure 1: Chronic tesofensine treatment more effectively induces a sustained weight loss and hypophagia in DIO rats on high-fat diet (energy density 5.24 kcal per g) as compared to ag matched normal-weight rats on standard chow (energy density 2.85 kcal per g).
In conclusion, research studies have shown that tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity.”
The above results suggest that tesofensine might have the potential to produce a weight loss twice that of currently anti-obesity drugs.
Appetite Sensations
Appetite is a person’s desire to eat food. It is distinct from hunger, which is the body’s biological response to a lack of food. A person can have an appetite even if their body is not showing signs of hunger, and vice versa. A person’s appetite can rise and fall due to a wide range of factors, sometimes causing people to eat less or more than their body needs.
Controlling appetite sensations is an important factor in improving the chances of successful maintenance of a reduced weight. In fact, weight loss is often accompanied by an increase in perceived hunger/appetite, which has been identified as an important predictor of weight relapse.
In addition to amplifying the already mentioned hedonic experience related to food, body weight reduction influences the release of some hormones involved in appetite regulation, such as leptin, ghrelin, peptide tyrosine-tyrosine, and glucagon-like peptide 1.
Research Example #1:
“In a recent study, researchers divided the trial into two parts (24 weeks each). Part 1 had a randomized, double-blind, placebo-controlled design and Part 2, an open-labeled, single-group, uncontrolled design. A drug-free period (12 ± 3 weeks) separated them. In Part 1, participants (n = 158) were assigned to 0.25, 0.5 or 1.0 mg tesofensine or placebo. Completers of Part 1 were invited to participate in Part 2 (n = 113), during which they all received 0.5 or 1.0 mg tesofensine.
Appetite sensations and a composite satiety score (CSS = satiety + fullness + (100 - hunger) + (100 - prospective food consumption) were assessed. In Part 1 tesofensine induced a dose-dependent increase in CSS at week 12 that correlated with weight loss during the 24 weeks (r = 0.36, P < 0.0001).
However, CSS diminished over time as weight loss progressed (e.g., for 1.0 mg; 52 ± 17 mm; 64 ± 13 mm; 55 ± 13 mm at baseline, week 12 and week 24, respectively). After drug withdrawal CSS returned to baseline values (50 ± 17 mm, in the whole sample.), despite the participants' reduced-weight state (-7.2 ± 6.7 kg, P < 0.0001). The reintroduction of tesofensine in Part 2 increased CSS again (56 ± 17 mm at week 60), regardless of initial treatment/weight loss. We postulate that enhanced satiety is involved in early weight loss.
Whether the attenuated effect on appetite seen after 24 weeks is due to a counteracting effect in the weight reduced state or whether the appetite suppressing effect of tesofensine per se diminishes over time is, however, still unclear.”
Research Example #2:
“Thirty-two healthy, overweight or moderately obese men were treated with 2.0 mg tesofensince daily for 7 days followed by an additional 7 days with 1.0 mg tesofensine daily or corresponding placebo (PL) in a randomized, controlled trial. They were instructed to maintain habitual food intake and physical activity throughout. Twenty-four-hour energy expenditure (24-h EE), fat oxidation and spontaneous physical activity were measured in a respiration chamber before and after treatment. Body composition was assessed by dual-energy X-ray absorption and appetite was evaluated by visual analogue scales in conjunction with a standardized dinner.
Despite efforts to keep body weight and composition constant, tesofensine induced a 1.8 kg weight loss above PL after 2 weeks' treatment (P<0.0001). Tesofensine also induced higher ratings of satiety and fullness and concomitantly lower prospective food intake than placebo. No significant effect of tesofensine on total 24-h EE could be demonstrated compared with PL, but higher energy expenditure was observed during the night period (4.6%; P<0.05) when adjusted for changes in body composition. Furthermore, tesofensine increased 24-h fat oxidation as compared with PL (18 g; P<0.001).
This study above found a clear effect on appetite sensation and a slightly reduced energy expenditure during the night after 14 days’ treatment with tesofensine. Thus, according to the research, the weight-reducing effect of tesofensine is potentially caused by a dual mechanism, mainly by decreasing appetite, but possibly also to some extent by stimulating thermogenesis.
References:
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