Patent Description:
Atypical antipsychotics are second-generation antipsychotics that are currently used to treat a variety of psychiatric conditions including schizophrenia, bipolar disorder, depression, and autism. Despite their documented efficacy and low risks for extrapyramidal symptoms, atypical antipsychotics are commonly associated with various adverse effects including obesity characterized by excessive bodyweight gain, lipid metabolism disorder, and glucose metabolism disorder. Patients taking for example olanzapine or clozapine have the highest risk to experience bodyweight gain. The rapid progression of body weight gain suggests a distinct etiology underlying the atypical antipsychotics-induced metabolic syndrome.

Unfortunately, the mechanisms underlying the various adverse effects such as body weight gain and metabolic disorders caused by the second generation atypical antipsychotics remain largely unknown despite extensive researches have been carried out.

Olanzapine has high binding affinities with multiple neurotransmitter receptors including dopamine D<NUM>, serotonin <NUM>-HT2A and <NUM>-HT2C, histamine H<NUM> receptors, and muscarinic M<NUM> and M<NUM> receptors. Numerous pharmacological adjunctive treatments have been tried to counteract olanzapine-induced weight gain. For example, co-treatment of olanzapine and betahistine (an HiR agonist and H<NUM>R antagonist) significantly reduced weight gain induced by olanzapine (<NPL>). Additional examples include muscarinic acetylcholine receptor Mi subtype antagonist telenzepine for treatment of olanzapine-induced weight gain (<CIT>), dopamine agonist pramipexole for preventing or reducing weight gain and associated metabolic syndrome in patients receiving atypical antipsychotic drugs including clozapine, olanzapine, quetiapine and risperidone (<CIT>), and the histamine H<NUM>-receptor antagonists selected from the group consisting of nizatidine, famoditine, cimetidine and ranitidine (<CIT>). However, the results with those agonists or antagonists are inconclusive or contradictory.

<NPL>") describes the use of N-acetyl cysteine in treating weight gain/metabolic disorder.

<CIT> describes a gold cluster for use in the treatment of glaucoma.

There remains a need for better strategies to counteract the adverse effects caused by the second generation antipsychotic drugs such as olanzapine and clozapine.

The present invention provides ligand-bound gold cluster as defined in the claims for use in the treatment of the adverse effects caused by an atypical antipsychotic in a subject as defined in the claims.

Certain embodiments of the present invention provide a ligand-bound gold cluster as defined in the claims for use in the treatment of the adverse effects caused by an atypical antipsychotic in a subject as defined in the claims, wherein the ligand-bound gold cluster comprises a gold core; and a ligand bound to the gold core. The atypical antipsychotic is one selected from the group consisting of olanzapine, and clozapine.

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the gold core has a diameter in the range of <NUM>-<NUM>. In certain embodiments, the gold core has a diameter in the range of <NUM>-<NUM>.

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the ligand is one selected from the group consisting of L-cysteine and its derivatives, D-cysteine and its derivatives, cysteine-containing oligopeptides and their derivatives, and other thiol-containing compounds as defined in the claims.

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the L-cysteine and its derivatives are selected from the group consisting of L-cysteine, N-isobutyryl-L-cysteine (L-NIBC), and N-acetyl-L-cysteine (L-NAC), and the D-cysteine and its derivatives are selected from the group consisting of D-cysteine, N-isobutyryl-D-cysteine (D-NIBC), and N-acetyl-D-cysteine (D-NAC).

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the cysteine-containing oligopeptides and their derivatives are cysteine-containing dipeptides, cysteine-containing tripeptides or cysteine-containing tetrapeptides.

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the cysteine-containing dipeptides are selected from the group consisting of L(D)-cysteine-L(D)-arginine dipeptide (CR), L(D)-arginine-L(D)-cysteine dipeptide (RC), L(D)-histidine-L(D)-cysteine dipeptide (HC), and L(D)-cysteine-L(D)-histidine dipeptide (CH).

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the cysteine-containing tripeptides are selected from the group consisting of glycine-L(D)-cysteine-L(D)-arginine tripeptide (GCR), L(D)-proline-L(D)-cysteine-L(D)-arginine tripeptide (PCR), L(D)-lysine-L(D)-cysteine-L(D)-proline tripeptide (KCP), and L(D)-glutathione (GSH).

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the cysteine-containing tetrapeptides are selected from the group consisting of glycine-L(D)-serine-L(D)-cysteine-L(D)-arginine tetrapeptide (GSCR), and glycine-L(D)-cysteine-L(D)-serine-L(D)-arginine tetrapeptide (GCSR).

In certain embodiments of the ligand-bound gold cluster for use in the treatment, the other thiol-containing compounds are selected from the group consisting of <NUM>-[(<NUM>)-<NUM>-methyl-<NUM>-thiol-<NUM>-oxopropyl]-L(D)-proline, thioglycollic acid, mercaptoethanol, thiophenol, D-<NUM>-trolovol, N-(<NUM>-mercaptopropionyl)-glycine, dodecyl mercaptan, <NUM>-aminoethanethiol (CSH), <NUM>-mercaptopropionic acid (MPA), and <NUM>-mercaptobenoic acid (p-MBA).

The objectives and advantages of the invention will become apparent from the following detailed description of preferred embodiments thereof in connection with the accompanying drawings.

Preferred embodiments according to the present invention will now be described with reference to the Figures, in which like reference numerals denote like elements.

The present invention may be understood more readily by reference to the following detailed description of certain embodiments of the invention.

As used herein, "administering" means oral ("po") administration, administration as a suppository, topical contact, intravenous ("iv"), intraperitoneal ("ip"), intramuscular ("im"), intralesional, intranasal or subcutaneous ("sc") administration, or the implantation of a slow-release device e.g., a mini-osmotic pump or erodible implant, to a subject. Administration is by any route including parenteral and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include the use of liposomal formulations, intravenous infusion and transdermal patches.

The terms "systemic administration" and "systemically administered" refer to administering a compound or composition to a mammal so that the compound or composition is delivered to sites in the body, including the targeted site of pharmaceutical action, via the circulatory system. Systemic administration includes oral, intranasal, rectal and parenteral (i.e. other than through the alimentary tract, such as intramuscular, intravenous, intra-arterial, transdermal and subcutaneous) administration, with the proviso that, as used herein, systemic administration does not include direct administration to the brain region by means other than via the circulatory system, such as intrathecal injection and intracranial administration.

As used herein, the terms "treating" and "treatment" refer to delaying the onset of, retarding or reversing the progress of, or alleviating or preventing either the disease or condition to which the term applies, or one or more symptoms of such disease or condition. The exemplary index is body weight gain herein. Depending on the patient, the treatment can result in a <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or greater, reduction of weight gain, e.g., in comparison to the weight gain experienced in the same or a different patient, or the average weight gain of a population of patients, receiving the antipsychotic without treatment over the same or a similar time period. In some patients, the treatment can result in reversal of antipsychotic-induced weight gain, that is, can effect weight loss. For example, some patients with treatment can lose <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>% of the antipsychotic-induced weight gain, e.g., returning to a weight maintained before administration of the antipsychotic without treatment.

The terms "patient," "subject" or "individual" interchangeably refers to a mammal, for example, a human or a non-human mammal, including primates (e.g., macaque, pan troglodyte, pongo), a domesticated mammal (e.g., felines, canines), an agricultural mammal (e.g., bovine, ovine, porcine, equine) and a laboratory mammal or rodent (e.g., rattus, murine, lagomorpha, hamster, guinea pig).

The phrase "adverse effects caused by atypical antipsychotics" refers to any of the known adverse effects including obesity characterized by obsessive body weight gain, lipid metabolism disorder, and glucose metabolism disorder. The phrase "antipsychotic-induced weight gain" refers to the side effect of weight gain experienced by patients receiving a therapeutic regiment of an atypical antipsychotic. The atypical antipsychotics include olanzapine and/or clozapine.

Olanzapine and clozapine are both characterized as non-selective acetylcholine-muscarinic receptor (Ach-M) antagonists.

The chemical designation of olanzapine is <NUM>-methyl-<NUM>-(<NUM>-methyl-<NUM>-piperazinyl)-<NUM>-thieno[<NUM>,<NUM>-b][<NUM>,<NUM>]benzodiazepine. The molecular formula is C<NUM>H<NUM>N<NUM>S, which corresponds to a molecular weight of <NUM>. Olanzapine is classified as a thienobenzodiazepine. The chemical structure is:
<CHM>.

The chemical designation of clozapine is <NUM>-chloro-<NUM>-(<NUM>-methyl-<NUM>-piperazinyl)-<NUM>-dibenzo(b,e)(<NUM>,<NUM>)diazepine. The molecular formula is C<NUM>H<NUM>ClN<NUM>, which corresponds to a molecular weight of <NUM>. The chemical structure is:
<CHM>.

Gold clusters (AuCs) are a special form of gold existing between gold atoms and gold nanoparticles. AuCs have a size smaller than <NUM>, and are composed of only several to a few hundreds of gold atoms, leading to the collapse of face-centered cubic stacking structure of gold nanoparticles. As a result, AuCs exhibit molecule-like discrete electronic structures with distinct HOMO-LUMO gap unlike the continuous or quasi-continuous energy levels of gold nanoparticles. This leads to the disappearance of surface plasmon resonance effect and the corresponding plasmon resonance absorption band (<NUM> ± <NUM>) at UV-Vis spectrum that possessed by conventional gold nanoparticles.

The present invention provides a ligand-bound AuC as defined in the claims.

The ligand-bound AuC as defined in the claims comprises a ligand and a gold core, wherein the ligand is bound to the gold core. The binding of ligands with gold cores means that ligands form stable-in-solution complexes with gold cores through covalent bond, hydrogen bond, electrostatic force, hydrophobic force, van der Waals force, etc In certain embodiments, the diameter of the gold core is in the range of <NUM> - <NUM>. In certain embodiments, the diameter of the gold core is in the range of <NUM> - <NUM>.

In certain embodiments, the ligand of the ligand-bound AuC is a thiol-containing compound or oligopeptide as defined in the claims. In certain embodiments, the ligand bonds to the gold core to form a ligand-bonded AuC via Au-S bond.

In certain embodiments, the ligand is L-cysteine, D-cysteine, or a cysteine derivative selected from N-isobutyryl-L-cysteine (L-NIBC), N-isobutyryl-D-cysteine (D-NIBC), N-acetyl-L-cysteine (L-NAC), or N-acetyl-D-cysteine (D-NAC).

In certain embodiments, the ligand is a cysteine-containing oligopeptide and its derivatives as defined in the claims. In certain embodiments, the cysteine-containing oligopeptide is a cysteine-containing dipeptide. In certain embodiments, the cysteine-containing dipeptide is L(D)-cysteine-L(D)-arginine dipeptide (CR), L(D)-arginine-L(D)-cysteine dipeptide (RC), or L(D)-cysteine-L-histidine dipeptide (CH). In certain embodiments, the cysteine-containing oligopeptide is a cysteine-containing tripeptide. In certain embodiments, the cysteine-containing tripeptide is glycine-L(D)-cysteine-L(D)-arginine tripeptide (GCR), L(D)-proline-L(D)-cysteine-L(D)-arginine tripeptide (PCR), or L(D)-glutathione (GSH). In certain embodiments, the cysteine-containing oligopeptide is a cysteine-containingtetrapeptide. In certain embodiments, the cysteine-containing tetrapeptide is glycine-L(D)-serine-L(D)-cysteine-L(D)-arginine tetrapeptide (GSCR) or glycine-L(D)-cysteine-L(D)-serine-L(D)-arginine tetrapeptide (GCSR).

In certain embodiments, the ligand is a thiol-containing compound as defined in the claims In certain embodiments, thiol-containing compound is <NUM>-[(<NUM>)-<NUM>-methyl-<NUM>-thiol-<NUM>-oxopropyl]-L(D)-proline, thioglycollic acid, mercaptoethanol, thiophenol, D-<NUM>-trolovol, dodecyl mercaptan, <NUM>-aminoethanethiol (CSH), <NUM>-mercaptopropionic acid (MPA), or <NUM>-mercaptobenoic acid (p-MBA).

Herein disclosed (not forming part of the invention) is a pharmaceutical composition for the treatment of a subject with adverse effects caused by an atypical antipsychotic including olanzapine and/or clozapine. In certain embodiments, the subject is human. In certain embodiments, the subject is a pet animal such as a dog.

In certain embodiments, the pharmaceutical composition comprises a ligand-bound AuC as disclosed above and a pharmaceutically acceptable excipient. In certain embodiments, the excipient is phosphate-buffered solution, or physiological saline.

The present invention provides the above disclosed ligand-bound AuCs for use in treating a subject with adverse effects caused by an atypical antipsychotic including olanzapine and/or clozapine using the above disclosed ligand-bound AuCs. In certain embodiments, the treatment comprises administering a pharmaceutically effective amount of ligand-bound AuCs to the subject. The pharmaceutically effective amount can be ascertained by routine in vivo studies.

In certain embodiments, in the treatment, the atypical antipsychotic drug and the ligand-bound AuCs can be co-administered. In certain embodiments, in the treatment, the atypical anti-psychotic drug and the ligand-bound AuCs can be administered separately by the same or different routes.

The following examples are provided for the sole purpose of illustrating the principles of the present invention.

As detected, the particle size of the powdery or flocculant substance obtained is smaller than <NUM> (distributed in <NUM>-<NUM> in general). No obvious absorption peak at <NUM>. It is determined that the obtained powder or floc is ligand-bound AuCs.

Taking ligand L-NIBC for example, the preparation and confirmation of AuCs bound with ligand L-NIBC are detailed.

Characterization experiment was conducted for the powder obtained above (L-NIBC-AuCs). Meanwhile, ligand L-NIBC-modified gold nanoparticles (L-NIBC-AuNPs) are used as control. The method for preparing gold nanoparticles with ligand being L-NIBC refers to the reference (<NPL>; <NPL>).

The test powders (L-NIBC-AuCs sample and L-NIBC-AuNPs sample)were dissolved in ultrapure water to <NUM>/L as samples, and then test samples were prepared by hanging drop method. More specifically, <NUM>µL of the samples were dripped on an ultrathin carbon film, volatized naturally till the water drop disappeared, and then observe the morphology of the samples by JEM-2100F STEM/EDS field emission high-resolution TEM.

The four TEM images of L-NIBC-AuNPs are shown in panels B, E, H, and K of <FIG>; the three TEM images of L-NIBC-AuCs are shown in panels B, E, and H of <FIG>.

The images in <FIG> indicate that each of L-NIBC-AuCs samples has a uniform particle size and good dispersibility, and the average diameter of L-NIBC-AuCs (refer to the diameter of gold core) is <NUM>, <NUM> and <NUM> respectively, in good accordance with the results in panels C, F and I of <FIG>. In comparison, L-NIBC-AuNPs samples have a larger particle size. Their average diameter (refer to the diameter of gold core) is <NUM>, <NUM>, <NUM> and <NUM> respectively, in good accordance with the results in panels C, F, I and L of <FIG>.

The test powders(L-NIBC-AuCs sample and L-NIBC-AuNPs sample) were dissolved in ultrapure water till the concentration was10mg·L-<NUM>,and the UV-vis absorption spectra were measured at room temperature. The scanning range was <NUM>-<NUM>, the sample cell was a standard quartz cuvette with an optical path of <NUM>, and the reference cell was filled with ultrapure water.

The UV-vis absorption spectra of the four L-NIBC-AuNPs samples with different sizes are shown in panels A, D, G and J of <FIG>, and the statistical distribution of particle size is shown in panels C, F, I and L of <FIG>; the UV-vis absorption spectra of three L-NIBC-AuCs samples with different sizes are shown in panels A, D and G of <FIG>, and the statistical distribution of particle size is shown in panels C, F and I of <FIG>.

<FIG> indicates that due to the surface plasmon effect, L-NIBC-AuNPs had an absorption peak at about <NUM>. The position of the absorption peak is relevant with particle size. When the particle size is <NUM>, the UV absorption peak appears at <NUM>; when the particle size is <NUM>, the UV absorption peak appears at <NUM>; when the particle size is <NUM>, the UV absorption peak appears at <NUM>, and when the particle size is <NUM>, the absorption peak appears at <NUM>. None of the four samples has any absorption peak above <NUM>.

<FIG> indicates that in the UV absorption spectra of three L-NIBC-AuCs samples with different particle sizes, the surface plasmon effect absorption peak at <NUM> disappeared, and two obvious absorption peaks appeared above <NUM> and the positions of the absorption peaks varied slightly with the particle sizes of AuCs. This is because AuCs exhibit molecule-like properties due to the collapse of the face-centered cubic structure, which leads to the discontinuity of the density of states of AuCs, the energy level splitting, the disappearance of plasmon resonance effect and the appearance of a new absorption peak in the long-wave direction. It could be concluded that the three powder samples in different particle sizes obtained above are all ligand-bound AuCs.

Infrared spectra were measured on a VERTEX80V Fourier transform infrared spectrometer manufactured by Bruker in a solid powder high vacuum total reflection mode. The scanning range is <NUM>-<NUM>-<NUM> and the number of scans is <NUM>. Taking L-NIBC-AuCs samples for example, the test samples were L-NIBC-AuCs dry powder with three different particle sizes and the control sample was pure L-NIBC powder. The results are shown in <FIG>.

<FIG> shows the infrared spectrum of L-NIBC-AuCs with different particle sizes. Compared with pure L-NIBC (the curve at the bottom), the S-H stretching vibrations of L-NIBC-AuCs with different particle sizes all disappeared completely at <NUM>-<NUM>-<NUM>, while other characteristic peaks of L-NIBC were still observed, proving that L-NIBC molecules were successfully bound to the surface of AuCs via Au-S bond. The figure also shows that the infrared spectrum of the ligand-bound AuCs is irrelevant with its size.

AuCs bound with other ligands were prepared by a method similar to the above method, except that the solvent of solution B, the feed ratio between HAuCl<NUM> and ligand, the reaction time and the amount of NaBH<NUM> added were slightly adjusted. For example: when L-cysteine, D-cysteine, N-isobutyryl-L-cysteine (L-NIBC) or N-isobutyryl-D-cysteine (D-NIBC) is used as the ligand, acetic acid is selected as the solvent; when dipeptide CR, dipeptide RC or <NUM>-[(<NUM>)-<NUM>-methyl-<NUM>-thiol-<NUM>-oxopropyl]-L-proline is used as the ligand, water is selected as the solvent, and so on and so forth; other steps are similar, so no further details are provided herein.

The present invention prepared and obtained a series of ligand-bound AuCs by the foregoing method. The ligands and the parameters of the preparation process are shown in Table <NUM>.

The samples listed in Table <NUM> are confirmed by the foregoing methods. The characteristics of nine different ligand-bound AuCs are shown in <FIG> (CR-AuCs), in <FIG> (RC-AuCs), in <FIG> (Cap-AuCs) (Cap denotes <NUM>-[(<NUM>)-<NUM>-methyl-<NUM>-thiol-<NUM>-oxopropyl]-L-proline), in <FIG> (GSH-AuCs), in <FIG>(D-NIBC-AuCs), in <FIG> (L-Cys-AuCs), in <FIG> (CSH-AuCs), in <FIG> (MPA-AuCs), and in <FIG> (p-MBA-AuCs). <FIG>showUV spectra (panel A), infrared spectra (panel B), TEM images (panel C), and particle size distribution (panel D).

The results indicate that the diameters of AuCs bound with different ligands obtained from Table <NUM> are all smaller than <NUM>. Ultraviolet spectra also show disappearance of peak at <NUM>±<NUM>, and appearance of absorption peak in other positions. The position of the absorption peak could vary with ligands and particle sizes as well as structures. In certain situations, there is no special absorption peak, mainly due to the formation of AuCs mixtures with different particles sizes and structures or certain special AuCs that moves the position of absorption peak beyond the range of UV-vis spectrum. Meanwhile, Fourier transform infrared spectra also show the disappearance of ligand thiol infrared absorption peak (between the dotted lines in panel B of <FIG>), while other infrared characteristic peaks are all retained, suggesting that all ligand molecules have been successfully bound to gold atoms to form ligand-bound AuCs, and the present invention has successfully obtained AuCs bound with the ligands listed in Table <NUM>.

All testing samples were prepared following the above described method with slight modification, and their quality was characterized using the above described methods.

<NUM> Establishment of olanzapine-induced adverse effects model and exploration of the inhibitory effect of different ligand-bound AuCs on olanzapine-induced weight gain and the dosage effect.

One hundred and forty-four (<NUM>)SPF female Sprague Dawley rats (<NUM>-<NUM> weeks) were purchased from the Experimental Animal Center of SiPeifu (Beijing) Biotechnology Co. All rats were kept in a barrier environment, the temperature was controlled at <NUM> ± <NUM>, and the interval between day and night was <NUM> hours, <NUM>: <NUM>-<NUM>: <NUM> as day, and <NUM>: <NUM>-<NUM>: <NUM> the next day as night. After one week of adaptive feeding, the rats were randomly divided into 12groups (n = <NUM>/group, making sure that the average body weight and food intake of each group of rats were nearly the same): negative control groups (CON, group <NUM>). ), Olanzapine model control group (OLZ, group <NUM>), Olanzapine+A1 high-dose group (OLZ+A1H, group <NUM>), Olanzapine+A1 low-dose group (OLZ+A1L, group <NUM>), Olanzapine+A2 high-dose group (OLZ+A2H, group <NUM>), Olanzapine+A2 low-dose group (OLZ+A2L, group <NUM>), Olanzapine+A3 high-dose group (OLZ+A3H, group <NUM>),Olanzapine+A3 low-dose group (OLZ+A3L, group <NUM>), Olanzapine+A4 high-dose group (OLZ+A4H, group <NUM>), Olanzapine+A5 high-dose group (OLZ+A5H, group <NUM>), Olanzapine+A6 high-dose group (OLZ+A6H, group <NUM>), and Olanzapine+B high-dose group (OLZ+B, group <NUM>). Groups <NUM>-12rats were given orally olanzapine (<NUM>/kg, tid (ter in die), administration time points: <NUM>:<NUM>, <NUM>:<NUM>, and <NUM>:<NUM>), and the negative control group (group <NUM>) was given an equal amount of placebo served as a control, where olanzapine was orally administered to rats in a pellet made of <NUM> of food (mixed with <NUM>% casein, <NUM>% corn starch, <NUM>% sucrose, and <NUM>% gelatin). Placebo is an equivalent amount of olanzapine-free food pills. From the first day of olanzapine (or placebo) administration, the olanzapine+drug high-dose groups were intraperitoneally injected with drug A1, A2, A3, A4, A5, A6 or B (<NUM>/kg, once a day), and olanzapine+drug low-dose groups were injected intraperitoneally with drug A1, A2 or A3 (<NUM>/kg, once a day). The negative control group and the olanzapine model control group were given by intraperitoneal injection of the same amount of physiological saline as a control. The same mode of administration was performed for <NUM> successive days. Animal feeding was measured every <NUM>, and animal weight was measured every <NUM> to observe the inhibitory effect of different doses of AuCs on olanzapine-induced weight gains.

On the 21st day of administration, all rats were fasted for <NUM>. Blood samples were collected from the tail vein of rats, and the fasting blood glucose value (<NUM>) of the rats was measured with a blood glucose meter (Johnson & Johnson One Touch Ultra, Johnson & Johnson (China) Medical Equipment Co. ), and the corresponding dose of glucose solution was injected intraperitoneally (<NUM>/kg), the blood glucose values were measured <NUM> minutes, <NUM> minutes, <NUM> minutes, and <NUM> minutes after administration of the glucose solution, and the area under the curve (AUC) of each mouse was calculated.

After the last administration, the rats were anesthetized with <NUM>% chloral hydrate. After blood samples were collected from the heart, the liver, mesenteric, perirenal, and periovary tissues were collected, weighed and stored at -<NUM>.

Statistical analysis was performed on all data using SPSS <NUM> statistical software. All data are expressed as mean±SEM, and the statistical difference is defined as P<<NUM>.

<NUM> Administration of gold cluster drug significantly reduced the rat weight gain and food intake caused by olanzapine.

Table <NUM> shows the body weight changes of the rats in negative control group, olanzapine model control group, high- and low-dose groups of three AuCs (A1, A2 and A3), and AuNP high-dose group. As shown in Table <NUM>, the initial body weights (IBW) of all groups of rats were nearly the same (<NUM> - <NUM>). After <NUM> day of drug administration, the final body weight (FBW) of the olanzapine model control group was significantly higher than that of the negative control group (P<<NUM>), indicating that the model was successfully established. Compared with the olanzapine model control group, the weights of the high-dose gold cluster drug groups (OLZ+A1H, OLZ+A2H and OLZ+A3H) were significantly lower (both P<<NUM>), and the weights of the low-dose gold cluster drug groups (OLZ+A1L, OLZ+A2L and OLZ+A3L) were apparently lower. At the same time, compared with the negative control group, the final body weight gain (BWG, i.e. the difference between the final body weight and the initial body weight) of the olanzapine model control group was extremely significantly increased (P<<NUM>); compared with the olanzapine model control group, the final body weight gains (BGW) of the high-dose gold cluster drug groups (OLZ+A1H, OLZ+A2Hand OLZ+A3H) were extremely significantly reduced (both P<<NUM>), and the final body weight gains (BGW) of the low-dose gold cluster drug groups (OLZ+A1L, OLZ+A2L and OLZ+A3L) were also significantly reduced (both P<<NUM>). The other three high dose gold cluster drug groups (OLZ+A4H, OLZ+A5H, and OLZ+A6H) showed similar results. However, compared with the olanzapine model control group, the final body weight (FBW) and final body weight gain (BGW) of the high-dose gold nanoparticle drug group (OLZ+B) were not significantly decreased (P> <NUM>).

In Table <NUM>, IBW: initial body weight; FBW: final body weight; BWG: body weight gain; CON: negative control group; OLZ: olanzapine model control group; OLZ+A1H: OLZ+A1 high-dose administration group; OLZ+A1L: OLZ+A1 low-dose administration group; OLZ+A2H: OLZ+A2 high-dose administration group; OLZ+A2L: OLZ+A2 low-dose administration group; OLZ+A3H: OLZ+A3 high-dose administration group; OLZ+A3L: OLZ+A3 low-dose administration group; OLZ+B: OLZ+B high-dose administration group; *: P<<NUM>, OLZ vs. CON; **: P< <NUM>, OLZ vs. CON; #: P<<NUM>, each administration group vs. OLZ; ##: P<<NUM>, each administration group vs. OLZ.

<NUM> Gold cluster drug administration significantly reduced the olanzapine-induced increase of mesenteric fat.

Olanzapine-induced weight gain can lead to fatty liver. Table <NUM> shows the changes of the liver weight and mesenteric fat of the rats in negative control group, olanzapine model control group, high- and low-dose groups of three AuCs (A1, A2 and A3), and AuNP high-dose group. As shown in Table <NUM>, compared with the negative control group, the olanzapine model control group increased liver weight, but there was no significant difference (P><NUM>). Compared with the olanzapine model control group, the different dose groups of the three gold cluster drugs can reduce liver weight, and the low-dose group of A1 and high-dose group of A3 showed a significant difference (P<<NUM>). Among the peripheral fats, compared with the negative control group, the olanzapine model control group significantly increased the accumulation of intestinal fat (P<<NUM>). Compared with the olanzapine model control group, both high and low doses of A1, A2 and A3 showed a dose-dependent reduction in the increase in olanzapine-induced peri-intestinal fat (the highest weight loss ratio was as high as <NUM>%). The other three high dose gold cluster drug groups (OLZ+A4H, OLZ+A5H, and OLZ+A6H) showed similar results. In summary, the gold cluster drugs can evidently reduce the fat increase caused by olanzapine, and show a certain dose dependence. However, gold nanoparticle high-dose group showed no significant change, indicating that gold nanoparticles are ineffective.

In Table <NUM>,CON: negative control group; OLZ: olanzapine model control group; OLZ+A1H: OLZ+A1 high-dose administration group; OLZ+A1L: OLZ+A1 low-dose administration group; OLZ+A2H: OLZ+A2 high-dose administration group; OLZ+A2L : OLZ+A2 low-dose administration group; OLZ+A3H: OLZ+A3 high-dose administration group; OLZ+A3L : OLZ+A3 low-dose administration group; OLZ+B: OLZ+B high-dose administration group; *: P<<NUM>, OLZ vs. CON; #: P<<NUM>, each administration group vs. OLZ; ##: P<<NUM> , each administration group vs. OLZ.

<NUM> Gold cluster drug administration significantly reduced the blood glucose increase caused by olanzapine.

Clinically, olanzapine administration can lead to elevated blood glucose and diabetes. <FIG> shows the blood glucose metabolism curves and area under the blood glucose curve (AUG) of the rats in negative control group, olanzapine model control group, high- and low-dose groups of three AuCs (A1, A2 and A3), and AuNP high-dose group.

This study found that the olanzapine model control group and the different administration groups did not significantly affect fasting blood glucose (P><NUM>). However, compared with the negative control group, after the glucose injection, the blood glucose level of the olanzapine model control group rats significantly increased at <NUM> minutes (P<<NUM>) and <NUM> minutes (P<<NUM>) after the intraperitoneal glucose injection, from <NUM> ± <NUM> mmol/L and <NUM> ± <NUM> mmol/L were increased to <NUM> ± <NUM> mmol/L and <NUM> ± <NUM> mmol/L, respectively (<FIG>). The area under the blood glucose curve (AUG) increased significantly from <NUM> ± <NUM> mmol/min to <NUM> ± <NUM> mmol/min (P<<NUM>, <FIG>). The above results indicate the significant effect of olanzapine administration on animal glucose metabolism disorder.

Compared with the olanzapine model control group, the blood glucose levels of the groups of three gold cluster drugs (A1, A2 and A3) were significantly reduced, especially in the high-dose groups. The blood glucose levels of the rats in the three high-dose groups significantly decreased at <NUM> minutes (both P<<NUM>), <NUM> minutes (both P<<NUM>), and <NUM> minutes (both P<<NUM>) after the glucose injection, and the blood glucose levels were close to that of the negative control group (<FIG>). Taking A1 as an example, the blood glucose values at these three time points decreased from <NUM> ± <NUM> mmol/L, <NUM> ± <NUM> mmol/L, and <NUM> ± <NUM> mmol/L of the olanzapine model control group to <NUM> ± <NUM> mmol/L, <NUM> ± <NUM> mmol/L and <NUM> ± <NUM> mmol/L respectively (<FIG>). In addition, the area under the blood glucose curve (AUG) of the three high-dose gold cluster drugs was also significantly lower than that of the olanzapine model control group (both P<<NUM>, <FIG>). Taking A1 (OLZ + A1H) as an example, the AUG value decreased from <NUM> ± <NUM> mmol/min in the olanzapine model control group (OLZ) to <NUM> ± <NUM> mmol/min. The blood glucose of rats in the three low-dose gold cluster drugs also decreased evidently at different time points, but both showed significant differences only at <NUM> minutes (P<<NUM>). The other three high dose gold cluster drug groups (OLZ+A4H, OLZ+A5H, and OLZ+A6H) showed similar results. This shows that gold cluster drugs can improve the blood glucose metabolism disorder caused by olanzapine in a dose-dependent manner.

However, the administration of gold nanoparticles (B) did not significantly decrease the blood glucose concentration (<FIG>) or the area under the blood glucose curve (AUG) (<FIG>) at different time periods. Therefore, it has no improvement effect on the blood glucose metabolism disorder caused by olanzapine.

In summary, long-term administration of gold clusters can significantly reduce the weight gain and fat increase caused by olanzapine, and significantly improve the lipid and glucose metabolism disorders caused by olanzapine, which provides the basis for later research and development of gold clusters as medications to reduce the second generation anti-psychotic drugs-induced adverse effects. However, gold nanoparticles have no such effects, and cannot be used as drugs for treating olanzapine-caused obesity.

Claim 1:
A ligand-bound gold cluster for use in the treatment of adverse effects caused by an atypical antipsychotic in a subject, wherein the ligand-bound gold cluster comprises:
a gold core; and
a ligand bound to the gold core; wherein
the atypical antipsychotic is olanzapine and/or clozapine;
the adverse effects caused by the atypical antipsychotic are selected from the group consisting of obesity characterized by excessive body weight gain, lipid metabolism disorder, and glucose metabolism disorder;
the ligand is one selected from the group consisting of L-cysteine and its derivatives, D-cysteine and its derivatives, cysteine-containing oligopeptides and their derivatives, and other thiol-containing compounds;
the L-cysteine and its derivatives are selected from the group consisting of L-cysteine, N-isobutyryl-L-cysteine (L-NIBC), and N-acetyl-L-cysteine (L-NAC);
the D-cysteine and its derivatives are selected from the group consisting of D-cysteine, N-isobutyryl-D-cysteine (D-NIBC), and N-acetyl-D-cysteine (D-NAC);
the cysteine-containing oligopeptides and their derivatives are cysteine-containing dipeptides, cysteine-containing tripeptides or cysteine-containing tetrapeptides; the cysteine-containing dipeptides are selected from the group consisting of L(D)-cysteine-L(D)-arginine dipeptide (CR), L(D)-arginine-L(D)-cysteine dipeptide (RC), L(D)-histidine-L(D)-cysteine dipeptide (HC), and L(D)-cysteine-L(D)-histidine dipeptide (CH); the cysteine-containing tripeptides are selected from the group consisting of glycine-L(D)-cysteine-L(D)-arginine tripeptide (GCR), L(D)-proline-L(D)-cysteine-L(D)-arginine tripeptide (PCR), L(D)-lysine-L(D)-cysteine-L(D)-proline tripeptide (KCP), and L(D)-glutathione (GSH); and the cysteine-containing tetrapeptides are selected from the group consisting of glycine-L(D)-serine-L(D)-cysteine-L(D)-arginine tetrapeptide (GSCR), and glycine-L(D)-cysteine-L(D)-serine-L(D)-arginine tetrapeptide (GCSR); and
the other thiol-containing compounds are selected from the group consisting of <NUM>-[(<NUM>)-<NUM>-methyl-<NUM>-thiol-<NUM>-oxopropyl]-L(D)-proline, thioglycollic acid, mercaptoethanol, thiophenol, D-<NUM>-trolovol, N-(<NUM>-mercaptopropionyl)-glycine, dodecyl mercaptan, <NUM>-aminoethanethiol (CSH), <NUM>-mercaptopropionic acid (MPA), and <NUM>-mercaptobenoic acid (p-MBA).