Curve In Rats Research Articles

Prediction of In Vivo Pharmacokinetic Parameters and Time-Exposure Curves in Rats Using Machine Learning from the Chemical Structure.

Animal pharmacokinetic (PK) data as well as human and animal in vitro systems are utilized in drug discovery to define the rate and route of drug elimination. Accurate prediction and mechanistic understanding of drug clearance and disposition in animals provide a degree of confidence for extrapolation to humans. In addition, prediction of in vivo properties can be used to improve design during drug discovery, help select compounds with better properties, and reduce the number of in vivo experiments. In this study, we generated machine learning models able to predict rat in vivo PK parameters and concentration-time PK profiles based on the molecular chemical structure and either measured or predicted in vitro parameters. The models were trained on internal in vivo rat PK data for over 3000 diverse compounds from multiple projects and therapeutic areas, and the predicted endpoints include clearance and oral bioavailability. We compared the performance of various traditional machine learning algorithms and deep learning approaches, including graph convolutional neural networks. The best models for PK parameters achieved R2 = 0.63 [root mean squared error (RMSE) = 0.26] for clearance and R2 = 0.55 (RMSE = 0.46) for bioavailability. The models provide a fast and cost-efficient way to guide the design of molecules with optimal PK profiles, to enable the prediction of virtual compounds at the point of design, and to drive prioritization of compounds for in vivo assays.

A novel preparative method for nanoparticle albumin-bound paclitaxel with high drug loading and its evaluation both in vitro and in vivo

We developed a novel preparative method for nanoparticle albumin-bound (nab) paclitaxel with high drug loading, which was based on improved paclitaxel solubility in polyethylene glycol (PEG) and self-assembly of paclitaxel in PEG with albumin powders into nanoparticles. That is, paclitaxel and PEG were firstly dissolved in ethanol, which was subsequently evaporated under vacuum. The obtained liquid was then mixed with human serum albumin powders. Thereafter, the mixtures were added into phosphate-buffered saline and nab paclitaxel suspensions emerged after ultrasound. Nab paclitaxel was finally acquired after dialysis and freeze drying. The drug loading of about 15% (W/V) were realized in self-made nab paclitaxel, which was increased by approximately 50% compared to 10% (W/V) in Abraxane. Now this new preparative method has been authorized to obtain patent from China and Japan. The similar characteristics of self-made nab paclitaxel compared to Abraxane were observed in morphology, encapsulation efficiency, in vitro release, X-ray diffraction analysis, differential scanning calorimetry analysis, and circular dichroism spectra analysis. Consistent concentration-time curves in rats, biodistributions in mice, anti-tumor activities in mice, and histological transmutation in mice were also found between Abraxane and self-made nanoparticles. In a word, our novel preparative method for nab paclitaxel can significantly improve drug loading, obviously decrease product cost, and is considered to have potent practical value.

The enhancement of N-acetylcysteine on intestinal absorption and oral bioavailability of hydrophobic curcumin

To solve the low oral bioavailability of curcumin (CUR) due to the limits imposed by gastrointestinal (GI) barrier, we constructed a nano delivery system to evaluate the effect of N-acetyl-L-cysteine (NAC) on intestinal absorption and oral bioavailability of CUR. CUR was first encapsulated in bovine serum albumin nanoparticles (CUR-BSA-NPs), and then was further modified by NAC (CUR-NBSA-NPs). In situ single-pass intestinal perfusion assay demonstrated that CUR-NBSA-NPs displayed excellent permeation and absorption rates in GI tract. Additionally, the distribution study in GI tract revealed that more NBSA-NPs were absorbed by intestinal segments compared to the BSA nanoparticles. Plasma concentration-time curves in rats showed that AUC0-t, Cmax and MRT0-t values of CUR after oral administration of CUR-NBSA-NPs were increased to 3.25-, 4.42-, and 1.43-fold compared with that of CUR suspension. In conclusion, NAC promotes oral absorption of CUR, thereby improving its oral bioavailability.

Borneol and poly (ethylene glycol) dual modified BSA nanoparticles as an itraconazole vehicle for brain targeting

Itraconazole (ITZ) can be used for the treatment of cryptococcus neoformans meningitis and aspergillus brain abscess. While, the inherent hydrophobicity of ITZ and the existence of blood brain barrier (BBB) limit its applications as a central nervous system drug. In this study, a novel brain targeting drug delivery system based on bovine serum albumin (BSA) was constructed for enhancing ITZ distribution in brain. Firstly, ITZ was loaded into BSA nanoparticles (ITZ-NPs) with 11.6% of drug loading. Subsequently, the nanoparticles were modified with borneol (BO) and polyethylene glycol (PEG) (PEG/BO-ITZ-NPs). The resulting nanoparticles retained their nanosize (186.3nm), uniform and spherical morphology, and negative surface charge (-21.03mV). Cell uptake studies showed that compared with ITZ-NPs, PEG/BO-ITZ-NPs had significantly increased uptake in bEnd.3 cells, and the increase in BO concentration was beneficial for the cellular uptake of NPs. Moreover, PEG/BO-ITZ-NPs displayed an approximately 3.5-fold higher area under the curve in rats and about 2-fold higher brain distribution in mice than that of Sporanox®, i.e. ITZ solubilized by hydroxylpropyl-β-cyclodetrin, after i.v. administration. In a word, BO and PEG dual modified BSA nanoparticles may potentially serve as an ITZ vehicle for brain targeting.

Understanding the cellular uptake and biodistribution of a dual-targeting carrier based on redox-sensitive hyaluronic acid-ss-curcumin micelles for treating brain glioma

The gliomas treatment is challenging due to the limits imposed by blood-brain barrier to the distribution of the drugs in the brain. Therefore, we designed a brain glioma targeting redox-sensitive hyaluronic acid (HA)-ss-curcumin (CUR) micelles. HA was conjugated to CUR through a disulfide bond, which could form micelles independently in aqueous solution. And we further increased the drug loading by loading free CUR. Brain penetration was achieved with Tween 80, whereas glioma-targeting was inclined by CD44-mediated endocytosis. Compared to the disulfide-free group, the redox-sensitive micelles exhibited rapid in vitro drug release under high glutathione conditions, significantly enhanced cell apoptosis and cellular uptake in G422 glioma cells. Redox-sensitive micelles displayed about 4.70-fold higher area under the curve in rats after intravenous injection in comparison to the free CUR and effectively accumulated in the brain. These findings suggest that redox-sensitive micelles could be a promising candidate to achieve brain targeted CUR delivery.

A strategy to improve the oral availability of baicalein: The baicalein-theophylline cocrystal

Baicalein (BE) is a flavonoid compound derived from the roots of Scutellaria baicalensis. It has widely been used as anti-oxidant, anti-virus, anti-bacteria, anti-inflammatory and anti-allergic therapies. Due to its poor water solubility (16.82 μg/ml), the therapeutic effectiveness and oral bioavailability of Baicalein are highly limited. The purpose of this study was to investigate the possibility of baicalein-theophylline (BE-TH) cocrystals to achieve the simultaneous enhancement in dissolution and oral bioavailability of BE. The cocrystal had the new characteristic of scanning electron microscopy, differential scanning calorimetry thermograms and X-ray powder diffraction. Compared with coarse powder of BE, BE-TH cocrystals had significantly improved the solubility of BE. The dissolution test showed that the BE-TH cocrystals demonstrated 2.2-fold and 7.1-fold higher rate of dissolution than that of BE coarse powder in HCl (pH = 1.2) and phosphate buffer (PBS, pH = 6.8), respectively. Moreover, the cocrystals exhibited a 5.86-fold higher area under the curve in rats after the oral administration. This investigation enriched the present understanding of cocrystals on their behavior in vitro and in vivo, and built the groundwork for future development of BE as a promising compound into efficacious drug products.

Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers.

The expression of multiple receptors on intestinal epithelial cells enables an actively targeted carrier to significantly enhance the oral delivery of payloads. Conjugating the receptors’ ligands on the surfaces of a particulate-delivery system allows site-specific targeting. Here, we used taurocholic acid (TCA) as a ligand for uptake of nanostructured lipid carriers (NLCs) mediated by a bile-acid transporter to improve oral bioavailability of curcumin (Cur). First, synthesis of TCA–polyethylene glycol 100–monostearate (S100-TCA) was carried out. Then, the physical and chemical properties of S100-TCA-modified Cur-loaded NLCs (Cur-TCA NLCs) with varying levels of S100-TCA modifications were investigated. Small particle size (<150 nm), high drug encapsulation (>90%), drug loading (about 3%), negative ζ-potential (−7 to −3 mV), and sustained release were obtained. In situ intestinal perfusion studies demonstrated improved absorption rate and permeability coefficient of Cur-TCA NLCs. Depending on the degree of modification, Cur-TCA NLCs displayed about a five- to 15-fold higher area under the curve in rats after oral administration than unmodified Cur NLCs, which established that the addition of S100-TCA to the NLCs boosted absorption of Cur. Further investigations of TCA NLCs might reveal a bright future for effective oral delivery of poorly bioavailable drugs.

Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats

“Bath salts” preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., “first-generation” cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., “second-generation” cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Behavioral evidence for the abuse potential of the novel synthetic cathinone alpha-pyrrolidinopentiothiophenone (PVT) in rodents.

Synthetic cathinones are chemical derivatives of cathinone that are pharmacologically similar to cocaine and methamphetamine. Recently, abuse of synthetic cathinones among young people has increased. The present study aimed to characterize the behavioral effects of alpha-pyrrolidinopentiothiophenone (PVT), an analog of alpha-pyrrolidinovalerophenone and second-generation synthetic cathinone, as well as to evaluate its abuse potential, using conditioned place preference, intravenous self-administration (SA), and drug discrimination paradigms in rodent models. Alpha-PVT produced a significant place preference in mice at doses of 10, 30, and 50mg/kg. In the SA experiment, alpha-PVT (0.1, 0.3, and 1.0mg/kg/infusion) produced an inverted U-shaped dose-effect curve in rats. Under a progressive ratio schedule of reinforcement, there appeared to be a positive relationship between alpha-PVT dose and the breakpoints for alpha-PVT reinforcement. Additionally, alpha-PVT fully substituted for the discriminative stimulus effects of both cocaine and methamphetamine in rats. Our results indicate that alpha-PVT has rewarding and reinforcing effects and shares the interoceptive effects of cocaine and methamphetamine. To the best of our knowledge, the present study is the first to show that alpha-PVT has reinforcing properties when delivered on its own, which suggests possible abuse liability in humans.

Bioavailability and biodistribution of nanodelivered lutein

The aim of the study was to evaluate the ability of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to enhance lutein bioavailability. The bioavailability of free lutein and PLGA-NP lutein in rats was assessed by determining plasma pharmacokinetics and deposition in selected tissues. Lutein uptake and secretion was also assessed in Caco-2 cells. Compared to free lutein, PLGA-NP increased the maximal plasma concentration (Cmax) and area under the time-concentration curve in rats by 54.5- and 77.6-fold, respectively, while promoting tissue accumulation in the mesenteric fat and spleen. In comparison with micellized lutein, PLGA-NP lutein improved the Cmax in rat plasma by 15.6-fold and in selected tissues by ⩾3.8-fold. In contrast, PLGA-NP lutein had a lower uptake and secretion of lutein in Caco-2 cells by 10.0- and 50.5-fold, respectively, compared to micellized lutein. In conclusion, delivery of lutein with polymeric NP may be an approach to improve the bioavailability of lutein in vivo.

Chronic Inflammatory Pain Prevents Tolerance to the Antinociceptive Effect of Morphine Microinjected into the Ventrolateral Periaqueductal Gray of the Rat

The ventrolateral periaqueductal gray (vlPAG) contributes to morphine antinociception and tolerance. Chronic inflammatory pain causes changes within the PAG that are expected to enhance morphine tolerance. This hypothesis was tested by assessing antinociception and tolerance following repeated microinjections of morphine into the vlPAG of rats with chronic inflammatory pain. Microinjection of morphine into the vlPAG reversed the allodynia caused by intraplantar administration of complete Freund's adjuvant and produced antinociception on the hot plate test. Although there was a gradual decrease in morphine antinociception with repeated testing, there was no evidence of tolerance when morphine- and saline-treated rats with hind paw inflammation were tested with cumulative doses of morphine. In contrast, repeated morphine injections into the vlPAG caused a rightward shift in the morphine dose-response curve in rats without hind paw inflammation, as would be expected with the development of tolerance. The lack of tolerance in complete Freund's adjuvant–treated rats was evident whether rats were exposed to repeated behavioral testing or not (experiment 2) and whether they were treated with 4 or 8 prior microinjections of morphine into the vlPAG (experiment 3). These data demonstrate that chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does disrupt the development of tolerance. PerspectiveThe present data show that induction of chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does attenuate the development of tolerance. This finding indicates that tolerance to opioids in rats with inflammatory pain is mediated by structures other than the vlPAG.

Recognition errors suggest fast familiarity and slow recollection in rhesus monkeys

One influential model of recognition posits two underlying memory processes: recollection, which is detailed but relatively slow, and familiarity, which is quick but lacks detail. Most of the evidence for this dual-process model in nonhumans has come from analyses of receiver operating characteristic (ROC) curves in rats, but whether ROC analyses can demonstrate dual processes has been repeatedly challenged. Here, we present independent converging evidence for the dual-process model from analyses of recognition errors made by rhesus monkeys. Recognition choices were made in three different ways depending on processing duration. Short-latency errors were disproportionately false alarms to familiar lures, suggesting control by familiarity. Medium-latency responses were less likely to be false alarms and were more accurate, suggesting onset of a recollective process that could correctly reject familiar lures. Long-latency responses were guesses. A response deadline increased false alarms, suggesting that limiting processing time weakened the contribution of recollection and strengthened the contribution of familiarity. Together, these findings suggest fast familiarity and slow recollection in monkeys, that monkeys use a “recollect to reject” strategy to countermand false familiarity, and that primate recognition performance is well-characterized by a dual-process model consisting of recollection and familiarity.

Influence of body weight and type of chow on the sensitivity of rats to the behavioral effects of the direct-acting dopamine-receptor agonist quinpirole

Amount and type of food can alter dopamine systems and sensitivity to drugs acting on those systems. This study examined whether changes in body weight, food type, or both body weight and food type contribute to these effects. Rats had free or restricted access (increasing, decreasing, or maintaining body weight) to standard (5.7% fat) or high-fat (34.3%) chow. In rats gaining weight with restricted or free access to high-fat chow, both limbs of the quinpirole yawning dose-response curve (0.0032-0.32 mg/kg) shifted leftward compared with rats eating standard chow. Restricting access to standard or high-fat chow (maintaining or decreasing body weight) decreased or eliminated quinpirole-induced yawning; within 1 week of resuming free feeding, sensitivity to quinpirole was restored, although the descending limb of the dose-response curve was shifted leftward in rats eating high-fat chow. These are not likely pharmacokinetic differences because quinpirole-induced hypothermia was not different among groups. PG01037 and L-741,626 antagonized the ascending and descending limbs of the quinpirole dose-response curve in rats eating high-fat chow, indicating D3 and D2 receptor mediation, respectively. Rats eating high-fat chow also developed insulin resistance. These results show that amount and type of chow alter sensitivity to a direct-acting dopamine-receptor agonist with the impact of each factor depending on whether body weight increases, decreases, or is maintained. These data demonstrate that feeding conditions, perhaps related to insulin and insulin sensitivity, profoundly impact the actions of drugs acting on dopamine systems.

An aqueous extract of Coptis chinensis (ACC) augments rat penile tissue erection

The aim of the present study was to investigate whether an aqueous extract of Coptis chinensis (ACC) augments penile erection in vivo and in ex vivo. In isolated endothelium‐intact rabbit corpus cavernosum preconstricted with phenylephrine, ACC (10−7−10−4 g/ml) relaxed penile smooth muscle in a dose‐dependent manner, which was inhibited by pretreatment with a nitric oxide synthase inhibitor, and a soluble guanylyl cyclase (sGC) inhibitor, respectively. In addition, incubation of endothelium intact rabbit corpus cavernosum tissues with ACC increased cGMP production in a dose‐dependent manner. ACC‐induced cGMP production was not blocked by pretreatment with L‐NAME or ODQ. Moreover, IBMX, a non‐selective phosphodiesterase (PDE) inhibitor, or zaprinast, a type 4, 5‐selective PDE inhibitor caused more increase in cGMP production than ACC alone. On the other hand, there are no significant difference between increases in penile tissue cGMP production induced ACC and co‐treated with ACC and IBMX or zaprinast, respectively. ACC (100, 500 mg/kg) also caused increase in intracavernous pressure and area under the curve in rats in a dose dependent manner. These results suggest that ACC maybe induce penile erection through the activation of penile tissue NO/cGMP system and/or inhibition of PDE in rat corpus cavernosum.

Dysfunction of the myocardium related to chronic insufficiency of nigro-striatal dopamine in rats and correction of these disturbances with melatonin

We studied the dependence of the maximum and final diastolic pressures in the left ventricle on the level of tension of the myocardium (the latter parameter was measured using a dosed increase in the volume of a polyethylene cartridge inserted into the cardiac ventricle) on isolated hearts of control rats and animals with chronic nigro-striatal (NS) dopamine (DA) insufficiency induced by unilateral injection of a selective neurotoxin, 6-hydroxydopamine, into the brain (model of hemiparkinsonism). In addition, we calculated the diastolic rigidity of the myocardium (the ratio between the increment of the final diastolic pressure and the enhancement of the volume of the cartridge in the left ventricle). We found that, under conditions of insufficiency of cerebral DA, the reactivity of the myocardium with respect to an increase in the volume loading, i.e., the ability of the cardiac muscle to intensify the contraction force upon expansion of the ventricle, is disturbed. The plateau of the Frank-Starling curve in rats with DA insufficiency was significantly smaller than that observed in control animals, and the rigidity of the myocardium increased. Therefore, we demonstrated that the state of the cardiac muscle becomes worse in rats with chronic NS DA insufficiency. A single injection of a powerful antioxidant and inhibitor of opening of the mitochondrial pore, melatonin, into animals with the model of hemiparkinsonism (1 h prior to the experiment) restored significantly the disturbed contractile function of the heart.

Impact of colostomy on intestinal microflora and bacterial translocation in young rats fed with heat-killed Lactobacillus acidophilus strain LB

A rat animal model of left colostomy was found to significantly impair the growth curve of rats. Assessment of the intestinal flora showed that colostomy mostly affects the cecal but not colonic microflora. Generally, the number of enterococci was increased in both ileum and cecum; cecal lactobacilli also rose, accounting for a promotion of lactic acid bacteria in colostomised rats. No significant differences between colostomised, laparotomised and control rats could be observed for the translocation of intestinal bacteria to internal organs of rats (i.e. spleen, kidneys, lungs or liver), whatever their diet. Heat-killed Lactobacillus acidophilus strain LB administration (dead probiotic bacteria) tended to exhibit a stimulatory effect on bifidobacteria, probably affecting the culture-medium fermentation substances included in the pharmaceutical product. This effect was abolished by laparotomy and colostomy. A trend towards a probiotic-like effect, not susceptible to colostomy, was also witnessed as counts of lactobacilli tended to increase in both cecum and colon of all animals fed with L. acidophilus LB.

The “inverted cup” — A novel in vitro release technique for drugs in lipid formulations

The aim of this study was to develop a membrane-free in vitro release method for drugs in lipid formulations. It was intended to be applicable to as wide a range as possible of preparations, independently of their polarity and viscosity. The principle of the novel technique is to keep the sample suspended in the release medium in an inverted glass cup, allowing a possible phase transition or swelling. Thirteen formulations containing bupivacaine, lidocaine and/or prilocaine in lipid vehicles with different physical properties were prepared and examined. When possible, in vitro release profiles obtained by the new method were compared to profiles obtained by earlier techniques. For three formulations of either bupivacaine or lidocaine in polar lipid formulations, in vitro release profiles were evaluated in relation to in vivo data, from nerve block and pharmacokinetic studies in rats. Preparations that could be investigated both by the “inverted cup” and by the earlier published “single drop” technique [L. Söderberg et al. J Pharm Pharmacol 2002; 54: 747–755] generally showed good agreement between the two release profiles. In the case of the polar lipid formulations, arterial blood concentration curves in rats could reasonably be predicted from the in vitro release profiles. In conclusion, the “inverted cup” technique should potentially be applicable to a wide range of lipid formulations of drugs, both for physico-chemical characterisation and for obtaining in vitro – in vivo correlations.

N-[ 18f]fluoroethylpiperidinyl, n-[ 18f]fluoroethylpiperidinemethyl and n-[ 18f]fluoroethylpyrrolidinyl esters as radiotracers for acetylcholinesterase

A series of N-fluoroethylpiperidinyl (1), N-fluoroethylpiperidinemethyl (2) and N-fluoroethylpyrrolidinyl (3) esters were synthesized and examined as new 18F-labeled radiotracers for measuring brain cholinesterase activity. The fluoroethyl group, instead of methyl group, results in slower in vitro enzymatic cleavage rates and higher selectivity for AChE. Based on metabolism in mouse blood and PET time-activity curves in rats, two radiotracers were identified as potential candidates for further in vivo evaluation in higher species.

Acute treatment with corticosteroids decreases IGF-1 and IGF-2 expression in the rat diaphragm and gastrocnemius.

Massive doses of methylprednisolone (M) or triamcinolone (T) induced diaphragmatic type IIx/b atrophy, resulting in a leftward shift of the force-frequency curve in rats (). To examine the role of insulin-like growth factors (IGFs) in these changes, IGF mRNA content was measured in costal diaphragm, gastrocnemius, and liver removed from 32 rats treated daily during 5 d either with saline (control, C and pair-fed, PF), M, or T (80 mg/kg). Blood samples were taken to measure IGF-1 serum levels. RNA levels were measured by Northern and dot-blots after hybridization with rat IGF-1 or IGF-2 cDNA probes labeled with alpha-32P. Compared with C (845 +/- 128 ng/ml), IGF-1 serum levels were significantly decreased in M (699 +/- 90 ng/ml, p < 0.001 versus C) and PF animals (505 +/- 33 ng/ml, p < 0.001 versus others) and even more so, in T-treated animals (273 +/- 134 ng/ml, p < 0.001 versus others). Along the same lines, IGF-1 expression in the liver was depressed after corticosteroid treatment and in PF, whereas IGF-2 mRNA content remained unchanged. Compared with C, the relative expression of IGF-1 mRNA in the diaphragm was depressed by 44% and 69% in the M and T groups, respectively (p < 0.0001 versus C), while it was unchanged in PF animals. In the gastrocnemius, IGF-1 expression was reduced after M and T (-51% and -59%, respectively, p < 0.0001 versus C) as well as in PF animals (-40%, p < 0.001 versus C). For IGF-2, a similar pattern of expression was found in the diaphragm and the gastrocnemius. Indeed, IGF-2 mRNA tended to decrease in corticosteroid-treated rats (NS) whereas it was unchanged in PF rats. We conclude that decreased IGF expression after corticosteroid treatment was similar in diaphragm and gastrocnemius and may be responsible for the diaphragmatic changes observed after steroid treatment.

Effect of Simmondsin Derivatives on Food Intake: Dose−Response Curves in Rats

Simmondsin is a food intake-reducing molecule found in the seeds of the jojoba plant (Simmondsia chinensis). Three naturally occurring analogues of simmondsin, simmondsin 2‘-trans-ferulate, 4-demethylsimmondsin, and 4,5-didemethylsimmondsin, were tested for anorexic properties, and dose response curves were constructed. Demethylsimmondsin and didemethylsimmondsin showed no anorexic properties, while simmondsin 2‘-trans-ferulate showed dose-dependent food intake-reducing activity, but, on an equimolar basis, was less active than simmondsin. The food intake-reducing activity of two synthetic derivatives of simmondsin, hydroxymethoxyphenylacetonitrile and simmondsinamide, was also determined, and both were found to be inactive. Keywords: Simmondsin; simmondsin derivatives; jojoba meal; food intake; rats