Noradrenergic and dopaminergic effects of (+)-amphetamine-like stimulants in the baboon Papio anubis.
ABSTRACT (+)-Amphetamine, (+/-)-ephedrine, and phentermine are commonly used appetite suppressants that release monoamines from nerve cells by acting as substrates for biogenic amine transporters. One key difference among the three drugs is their selectivity for norepinephrine (NE) release vs. dopamine (DA) release. The NE/DA selectivity ratios for these drugs as determined in vitro [(EC50 NE(-1))/(EC50 DA(-1))] are (+/-)-ephedrine (18.6) > phentermine (6.7) > (+)-amphetamine (3.5). The in vitro data suggest that when administered in vivo, these stimulants might differ in their ability to release DA from nerve terminals in the brain. To test this hypothesis, noradrenergic effects (i.e., plasma NE) and dopaminergic effects (i.e., central DA release) were assessed when each drug was administered intravenously (1.5 mg/kg) to anesthetized baboons. Central DA release was determined via positron emission tomography using the method of [11C]raclopride displacement. In the present investigation, high doses of these stimulants increased plasma NE and DA in parallel, but only (+)-amphetamine released central DA from neurons and decreased plasma prolactin. None of the drugs altered plasma amine metabolite levels, indicating no inhibition of monoamine oxidase activity at the administered doses. Plasma drug levels measured in baboons were higher than those measured in human patients taking prescribed doses of the drugs. Viewed collectively, the present data indicate that typical clinical doses of phentermine and (+/-)-ephedrine may not release central DA in humans, a hypothesis that should ultimately be tested in controlled clinical studies.
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ABSTRACT: Hypothalamic neuropeptide Y (NPY) has been reported to involve in regulating behavioral response of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored if protein kinase C (PKC)-delta signaling participated in this regulation. Moreover, possible roles of anti-free radical enzyme catalase (CAT) and nitrogen oxide synthase (NOS) were also examined. Rats were treated daily with PPA for 4 days. Changes in food intake and hypothalamic NPY, PKCdelta, CAT, and NOS contents were assessed and compared. Results showed that PKCdelta and CAT increased during PPA treatment, which were concomitant with decreases in NPY content and food intake, while the change of NOS was expressed differently. Moreover, PKCdelta knockdown could modify PPA anorexia as well as NPY and CAT expression, while NOS expression remained unchanged. Furthermore, pre-treatment with NOS inhibitor could modify both PPA anorexia and NPY content. It is suggested that PKCdelta participates in the anorectic response of PPA via the modulation of NPY and CAT, while NOS contribute to this modulation via a different mechanism during PPA treatment. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the therapeutic research of PPA and other anti-obesity drugs.Journal of Neurochemistry 08/2010; 114(4):1217-30. DOI:10.1111/j.1471-4159.2010.06843.x · 4.24 Impact Factor
Article: Phentermine cardiovascular safety[Show abstract] [Hide abstract]
ABSTRACT: A letter to the editor “Cusp tear in bicuspid valve possibly caused by phentermine” published in volume 106 (2006) stated “Phentermine is known to cause valvular disease with prolonged use.” There is no evidence that phentermine causes valvulopathy. Phentermine is the most widely used anti-obesity drug. In view of the serious cardiovascular risks associated with obesity, it is important to clarify that phentermine is a safe and effective anti-obesity medication.The American journal of emergency medicine 10/2009; 27(8):1010-3. DOI:10.1016/j.ajem.2009.07.014 · 1.15 Impact Factor
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ABSTRACT: Hypothalamic neuropeptide Y (NPY) is an appetite stimulant in the brain. Although regulation of NPY expression has been reported to contribute to the appetite-suppressing effect of phenylpropanolamine (PPA), it is still unknown if protein kinase C (PKC) is involved in this effect. Rats were daily treated with PPA for 4 days. Changes in food intake, hypothalamic NPY, PKC, and proopiomelanocortin (POMC) mRNA levels were assessed and compared. Results showed that the NPY gene was down-regulated following PPA treatment, which was parallel with the decrease of feeding. Moreover, several isotypes of PKC mRNA level (alpha, betaI, betaII, gamma, delta, eta, lambda, epsilon, and zeta) were changed. Among these, alpha, delta, and lambda PKC were up-regulated along with POMC gene expression which coincided with down-regulation of the NPY gene. To further determine if PKCalpha was involved, infusions of antisense oligonucleotide into the cerebroventricle were performed at 1 h before daily PPA treatment in free-moving rats. Results showed that PKCalpha knock-down could modify both anorexia induced by PPA and the NPY mRNA levels. Moreover, PKCalpha knock-down could also modify superoxide dismutase (SOD) gene expression. It is suggested that PKCalpha participates in the regulation of PPA-mediated appetite suppression via the modulation of NPY and SOD gene expression.Journal of Neurochemistry 02/2009; 108(6):1495-506. DOI:10.1111/j.1471-4159.2009.05909.x · 4.24 Impact Factor