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- What is the main purpose of the compounds and compositions described in the patent?
The compounds and compositions are designed to reduce or prevent the abuse and overdose of amphetamine.
- For what disorders are these abuse-resistant amphetamine formulations particularly useful?
These formulations are particularly useful for treating attention deficit hyperactivity disorder (ADHD), ADD, narcolepsy, and obesity.
- How does the invention reduce the oral abuse liability of amphetamine?
The invention maintains oral bioavailability of amphetamine at therapeutically useful doses. However, at higher doses, bioavailability is substantially reduced, thereby reducing oral abuse liability.
- Besides oral administration, what other routes of administration does the invention aim to decrease bioavailability for, and why?
The invention also aims to decrease the bioavailability of amphetamine by parenteral routes, such as intravenous or intranasal administration, to further limit abuse liability. These routes are commonly used for drug abuse due to their rapid onset of effects.
- What is the significance of lysine in the context of this patent?
The patent describes 'Abuse Resistant Lysine Compounds,' suggesting that lysine is chemically linked to amphetamine or a related compound. This linkage likely alters the drug's pharmacokinetic properties, such as its rate of absorption or metabolism, to reduce its abuse potential. The specific mechanism would involve the enzymatic cleavage of the lysine moiety to release the active amphetamine.
- Based on the references cited, what is the role of peptide transporters (like PEPT1) in drug delivery, and how might this be relevant to the invention?
The cited references suggest that peptide transporters, such as PEPT1, can be utilized to enhance the absorption of drugs by the intestinal cells. The prodrug approach, where a drug is linked to an amino acid or peptide, can exploit these transporters. In the context of this invention, linking amphetamine to lysine might facilitate its absorption via PEPT1 at therapeutic doses, while the high doses required for abuse might
overwhelm the transporter, leading to reduced bioavailability and abuse potential.
- What is a prodrug, and how does the concept of a prodrug relate to the abuse-resistant properties of the lysine-amphetamine compounds?
A prodrug is a pharmacologically inactive compound that is converted into an active drug through metabolic processes within the body. In the context of lysine-amphetamine compounds, the lysine acts as a promoiety. The compound is inactive until the lysine is cleaved off, releasing the active amphetamine. The rate and extent of this cleavage can be controlled to achieve the desired therapeutic effect while minimizing the potential for abuse. For example, slow release or incomplete conversion at high doses could reduce the 'rush' associated with abuse.
- What is the relevance of US patent number 4,000,280 A to this patent?
Without knowing the specific content of US patent number 4,000,280 A, it's difficult to determine its exact relevance. However, given that it is listed under 'References Cited,' it likely describes prior art related to amphetamine compounds, drug delivery systems, or methods for reducing drug abuse potential. It could disclose similar compounds, formulations, or strategies that the current invention builds upon or distinguishes itself from.
- What is the significance of the 'terminal disclaimer' mentioned in the patent?
A terminal disclaimer is a statement filed by a patent applicant to disclaim a portion of the term of a patent. It is often used when there is a potential issue of double patenting, meaning that the invention claimed in the current application might be considered too similar to an invention claimed in an earlier patent owned by the same inventor or assignee. By filing a terminal disclaimer, the applicant agrees that the current patent will expire at the same time as the earlier patent, thus avoiding an extension of patent protection beyond what is legally permissible.
- What does the filing date of May 7, 2007, signify in the context of this patent?
The filing date of May 7, 2007, is the date on which the patent application was officially submitted to the United States Patent and Trademark Office (USPTO). This date is crucial because it establishes the priority date for the invention. The priority date is used to determine whether the invention is novel and non-obvious compared to prior art. Any publication or invention that predates this filing date can be used as evidence against the patentability of the invention.
- What is Paclitaxel conjugated with in the study by Li, C. et al. (1998)?
According to Rawitch, Allen B., et al. (1984), the significance of the thyroxine-containing amino acid sequences they isolated from bovine, ovine, and porcine thyroglobulins is that they are identical. This suggests a conserved and essential role for these sequences in thyroid hormone synthesis and function across different species.
- What is the focus of the study by Zunino, Franco, et al. (1982) regarding daunorubicin?
The study by Zunino, Franco, et al. (1982) focuses on the anti-tumor activity of daunorubicin linked to poly-L-aspartic acid. This conjugation strategy aims to improve the drug's delivery to tumor cells and enhance its anti- cancer effects.
- Based on the information provided, what is the general purpose of conjugating drugs to amino acids or peptides?
Based on the provided information, the general purpose of conjugating drugs to amino acids or peptides is to improve their pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion (ADME), enhance their cellular uptake, target them to specific tissues or cells, overcome drug resistance, and ultimately improve their therapeutic efficacy and reduce side effects. This is achieved by exploiting the properties of amino acids and peptides, such as their ability to interact with specific transporters or receptors.
- What is the focus of the research by Okada, Masahiko, et al. (1997)?
The research by Okada, Masahiko, et al. (1997) focuses on the synthesis of glycopeptide-conjugates via ring-opening polymerization of sugar- substituted O-amino acid N-carboxyanhydrides (GlycoNCAs). This approach explores a method for creating novel glycopeptide structures with potential applications in drug delivery and biomaterials.
- What is Lisdexamfetamine Dimesylate primarily used for?
Lisdexamfetamine Dimesylate is primarily used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
- Lisdexamfetamine is a prodrug. What does this mean in the context of its mechanism of action?
As a prodrug, Lisdexamfetamine Dimesylate is inactive until it is metabolized in the body. Specifically, it is converted to d-amphetamine and L-lysine. The d-amphetamine is the active component that provides the therapeutic effect for ADHD.
- According to the provided texts, what is the significance of Lisdexamfetamine's prodrug nature in relation to its abuse potential?
The prodrug nature of Lisdexamfetamine Dimesylate is significant because it is designed to reduce the potential for abuse. Because the active drug, d-
amphetamine, is released gradually after metabolism, it is less likely to produce the rapid, intense high associated with direct administration of amphetamines. Studies have been conducted to evaluate the abuse liability of intravenous Lisdexamfetamine Dimesylate in adult stimulant abusers.
- What are some common side effects observed in children treated with Lisdexamfetamine Dimesylate for ADHD?
While the provided text doesn't explicitly list common side effects, it does mention studies focusing on the long-term effectiveness and safety of Lisdexamfetamine Dimesylate in school-aged children with ADHD. It also references tolerability studies. To determine specific side effects, one would need to consult the referenced studies or other clinical resources.
- How does food intake affect the bioavailability of Lisdexamfetamine?
The text mentions a study on the relative bioavailability of Lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers. This suggests that food intake can influence the absorption and bioavailability of the drug. The study likely details the specific impact of food on bioavailability.
- What is the role of cytochrome P450 enzymes in the metabolism of Lisdexamfetamine?
The text mentions an evaluation of the cytochrome P450 inhibition potential of Lisdexamfetamine in human liver microsomes. This indicates that the study investigated whether Lisdexamfetamine inhibits these enzymes, which are crucial for drug metabolism. However, the text does not explicitly state whether cytochrome P450 enzymes are directly involved in the metabolism of Lisdexamfetamine itself, but rather if Lisdexamfetamine inhibits these enzymes.
- What is the significance of the analog classroom study mentioned in the context?
The analog classroom study is significant because it provides a controlled environment to assess the efficacy of Lisdexamfetamine Dimesylate in children with ADHD. It allows researchers to observe and measure the drug's effects on attention, behavior, and academic performance in a setting that simulates a real classroom.
- What is the purpose of the ADHD Rating Scale (ADHD RS) as mentioned in the text?
The ADHD Rating Scale (ADHD RS) is used to assess the symptoms and severity of ADHD. The text mentions a study evaluating the internal consistency and validity of the ADHD RS with adult ADHD prompts, suggesting its use in both children and adults.
- Based on the figures provided, compare and contrast the absorption rates of d-amphetamine and L-lysine-d-amphetamine after oral administration.
Based on figures such as 29A, 29B, 30A and 30B, L-lysine-d-amphetamine appears to have a slower absorption rate compared to d-amphetamine after oral administration. The concentration of d-amphetamine tends to rise more quickly and reach a higher peak than L-lysine-d-amphetamine in the initial hours after administration. This suggests that the L-lysine component may delay the release and absorption of d-amphetamine.
- What provisional patent applications does this patent application claim benefit from?
This application claims the benefit of U.S. Provisional Patent Application Nos. 60/473,929, filed May 29, 2003 and 60/567,801, filed May 4, 2004.
- Based on the data presented in the figures, what is a potential advantage of using L-lysine-d-amphetamine over d-amphetamine?
Based on the figures, a potential advantage of L-lysine-d-amphetamine is a potentially smoother and more prolonged release of d-amphetamine, which could lead to a reduced risk of abuse or side effects associated with rapid increases in d-amphetamine concentration. The figures suggest a slower absorption and potentially a more sustained release profile for L-lysine-d- amphetamine compared to d-amphetamine.
- Referring to Figures 54A and 54B, compare the concentration profiles of L-lysine-d-amphetamine with Adderall XR.
Figures 54A and 54B show concentration profiles of L-lysine-d- amphetamine compared to Adderall XR (d-amphetamine and l- amphetamine). The figures suggest that L-lysine-d-amphetamine may have a different release profile compared to Adderall XR, potentially leading to a different pharmacokinetic profile. A detailed comparison would require careful examination of the specific concentration values and time points in the figures.
- Based on the figures, what is the general trend observed in the concentration of amphetamine over time after administration of L- lysine-d-amphetamine?
The general trend observed in the figures is that after administration of L- lysine-d-amphetamine, the concentration of amphetamine in the body gradually increases over time, reaches a peak, and then slowly decreases. The rate of increase and the peak concentration can vary depending on the route of administration, dosage, and the specific formulation.
- What is the primary use of amphetamine as described in the text?
Amphetamine is prescribed for the treatment of various disorders, including attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy. It stimulates the central nervous system.
- According to the Controlled Substances Act (CSA), what schedule is amphetamine classified under and why?
Amphetamine is classified as a Schedule II drug under the Controlled Substances Act (CSA). This classification is reserved for drugs that have accepted medical use but also have the highest potential for abuse.
- What is the black box warning that the FDA requires on amphetamine product package inserts?
The FDA requires the following black box warning: "AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NONTHERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY."
- How does the invention described in the text aim to reduce the abuse potential of amphetamine?
The invention aims to reduce the abuse potential of amphetamine through several methods: by creating amphetamine conjugate compounds that release amphetamine gradually over an extended period of time when taken orally, by substantially decreasing the bioavailability of amphetamine when taken at doses above the intended prescription, and by making the compositions resistant to abuse by parenteral routes of administration, such as intravenous 'shooting,' intranasal 'snorting,' or inhalation 'smoking.'
- What are some of the routes of administration that substance abusers use to abuse amphetamine, as mentioned in the text?
The text mentions that substance abusers may abuse amphetamine through parenteral routes of administration, such as intravenous 'shooting,' intranasal 'snorting,' or inhalation 'smoking.' They may also swallow tablets whole or crush and snort them.
- What is the mechanism by which sustained-release formulations of amphetamine work, and what are their shortcomings?
Sustained-release formulations typically contain drug particles mixed with or covered by a polymer material that resists degradation in the stomach and/or intestine. Release occurs through leeching, erosion, rupture, or diffusion. Shortcomings include uneven release and susceptibility to breakdown, allowing for abuse of the active ingredient.
- What is the purpose of covalently attaching amphetamine to a chemical moiety, according to the text?
The purpose of covalently attaching amphetamine to a chemical moiety is to create a prodrug form. This means the molecule is converted into its active
The covalent attachment reduces overdose potential through multiple mechanisms. First, it can decrease the toxicity of amphetamine at doses above therapeutic levels while maintaining pharmaceutical activity within the normal dose range. Second, it can decrease the rate or overall amount of absorption of amphetamine when given at supratherapeutic doses. Finally, it can increase the rate or overall amount of clearance of amphetamine when given at doses above those considered therapeutic. Saturation of the processes responsible for amphetamine release may also occur at higher doses, diminishing the release of harmful levels of active amphetamine.
- What are some examples of amino acids or peptides that can be used as the chemical moiety covalently attached to amphetamine?
The text mentions several examples, including single amino acids like Lysine (Lys), Serine (Ser), and Phenylalanine (Phe), as well as dipeptides and tripeptides such as Gly-Gly-Gly, Leu-Ser, and Leu-Glu. Homopolymers of Glutamic acid (Glu) and Leucine (Leu), and heteropolymers of (Glu)n-Leu- Ser are also mentioned.
- According to the text, what are the therapeutic applications of the described amphetamine compositions?
The text states that the compositions can be used for treating patients suffering from attention deficit hyperactivity disorder (ADHD), narcolepsy, or obesity.
- Explain the significance of the 'AUC' and 'Cmax' values in the context of the invention.
The invention aims to provide a therapeutically bioequivalent Area Under the Curve (AUC) compared to amphetamine alone, meaning the overall exposure to the drug is similar. However, it seeks to avoid a Cmax (maximum concentration) that results in euphoria when taken orally. This is achieved through the controlled release mechanism provided by the covalent attachment.
- What is the preferred characteristic of the carrier in terms of its amino acid composition?
In a preferred embodiment, the carrier, whether a single amino acid, dipeptide, tripeptide, oligopeptide, or polypeptide, comprises only naturally occurring amino acids.
- How does the invention address the issue of conventional extended-release formulations being susceptible to abuse?
Conventional extended-release formulations, when crushed, release the entire amphetamine content immediately, leading to a 'rush' effect if injected or snorted. The invention addresses this by covalently attaching amphetamine to a chemical moiety, requiring hydrolysis for release. This hydrolysis is time-dependent and less effective via parenteral routes, thus
preventing the immediate release of a large dose and reducing the potential for abuse.
- Describe the difference in amphetamine release between oral and parenteral routes when using the covalently attached amphetamine.
The composition provides oral bioavailability due to the hydrolysis of the covalent linkage following oral administration, allowing amphetamine to become available in its active form over an extended period. However, release of amphetamine is diminished or eliminated when delivered by parenteral routes (e.g., injection, intranasal).
- Explain the concept of 'saturation' in the context of amphetamine release from the chemical moiety.
At higher doses of the covalently attached amphetamine, the processes responsible for amphetamine release (likely enzymatic hydrolysis) may become saturated. This means that the rate of release plateaus, and increasing the dose further does not proportionally increase the amount of active amphetamine released. This saturation effect contributes to the reduced potential for overdose.
- What is L-lysine-d-amphetamine also known as?
L-lysine-d-amphetamine is also known as Lys-Amp, Lys-Amph, Lysine Amphetamine, KAMP, K-amphetamine, or 2,6-diaminohexanoic acid-(1- methyl-2-phenylethyl)-amide.
- According to the document, what is the purpose of covalently modifying amphetamine?
The purpose of covalently modifying amphetamine is to decrease its potential for causing overdose or abuse. This is achieved by decreasing its pharmacological activity at doses above those considered therapeutic, while retaining similar activity at therapeutic doses.
- What chemical moieties can be attached to amphetamine through covalent modification, according to the text?
According to the text, the chemical moiety attached to amphetamine can include at least amino acid(s), peptide(s), glycopeptide(s), carbohydrate(s), lipid(s), nucleoside(s), or Vitamin(s).
- What are some examples of carbohydrates that can be used as chemical moieties?
Examples of carbohydrates include sugars, starches, cellulose, and related compounds. More specific examples include fructose, glucose, lactose, maltose, sucrose, glyceraldehyde, dihydroxyacetone, erythrose, ribose, ribulose, Xylulose, galactose, mannose, Sedoheptulose, neuraminic acid, dextrin, and glycogen.
According to the patent, covalently binding amphetamine to a chemical moiety aims to decrease the pharmacological activity until the amphetamine is released, reduce the rate of absorption, reduce amphetamine toxicity, prevent spiking or increased blood serum concentrations, and prevent a toxic release profile.
- What does 'in a manner inconsistent with the manufacturer's instructions' mean in the context of this patent?
In the context of this patent, 'in a manner inconsistent with the manufacturer's instructions' includes consuming amounts greater than described on the label or ordered by a licensed physician, and/or altering the dosage formulation (e.g., crushing, breaking, melting, separating) such that the composition may be injected, inhaled, or smoked.
- What are some examples of chemical moieties that can be attached to amphetamine?
Examples of chemical moieties that can be attached to amphetamine include amino acids, peptides, lipids, carbohydrates, glycopeptides, nucleic acids, and vitamins.
- What is the preferred range for the number of chemical moieties attached to amphetamine?
The preferred range is between one to 8 chemical moieties.
- According to the patent, what are some examples of unnatural amino acids that can be used?
The patent lists aminohexanoic acid, biphenylalanine, cyclohexylalanine, cyclohexylglycine, diethylglycine, dipropylglycine, 2,3-diaminoproprionic acid, homophenylalanine, homoserine, homotyrosine, naphthylalanine, norleucine, ornithine, phenylalanine(4-fluoro), phenylalanine(2,3,4,5, pentafluoro), phenylalanine(4-nitro), phenylglycine, pipecolic acid, sarcosine, tetrahydroisoquinoline-3-carboxylic acid, and tert-leucine as examples of unnatural amino acids.
- Explain how the attachment of a chemical moiety to amphetamine can prevent stimulant activity.
The attachment of certain chemical moieties can diminish or prevent binding to biological target sites. Further, the covalent modification may prevent stimulant activity by preventing the drug from crossing the blood- brain barrier. Preferably, absorption of the composition into the brain is prevented or substantially diminished and/or delayed when delivered by routes other than oral administration.
- What is the significance of the phrase 'decreased', 'reduced', 'diminished' or 'lowered' in the context of pharmacological activity?
The phrases 'decreased', 'reduced', 'diminished' or 'lowered' are meant to include at least a 10% change in pharmacological activity, with greater
percentage changes being preferred for reduction in abuse potential and overdose potential. The change may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or increments therein.
- Describe the composition for preventing a C spike for amphetamine when taken by means other than orally.
The composition for preventing a C spike for amphetamine when taken by means other than orally while still providing a therapeutically effective bioavailability curve if taken orally comprises an amphetamine which has been covalently bound to a chemical moiety.
- What is Formula I and what do A, X, n, Z, and m represent?
Formula I represents a compound where: A is an amphetamine as defined in the patent; X is a chemical moiety as defined in the patent; n is between 1 and 50 and increments thereof; Z is a further chemical moiety different from X which acts as an adjuvant; and m is between 1 and 50 and increments thereof.
- Explain the concept of steady-state serum release curve in the context of this patent and its importance.
The concept of a steady-state serum release curve refers to a drug release profile where the concentration of amphetamine in the blood remains relatively constant over time. This is important because it provides a therapeutically effective bioavailability while preventing spiking or increased blood serum concentrations compared to unbound amphetamine, especially when given at doses exceeding the therapeutic range. This helps to reduce toxicity and prevent overdose.
- What is the purpose of covalently binding a chemical moiety to amphetamine in the described compositions?
The purpose is to increase the rate of clearance of amphetamine when given at doses exceeding the therapeutic range, reduce toxicity compared to unbound amphetamine, and reduce or eliminate the possibility of overdose by various routes of administration (oral, intranasal, injection, inhalation).
- Name three hydrophilic polymers suitable for use in sustained- release formulations of amphetamine conjugates.
Three hydrophilic polymers suitable for use in sustained-release formulations are hydroxypropyl methylcellulose, methylcellulose, and carboxymethylcellulose.
- What are some examples of pharmaceutical additives that can be included in amphetamine conjugate formulations?
Pharmaceutical additives include lubricants (e.g., magnesium stearate), colorants (e.g., Emerald Green Lake), binders (e.g., sucrose), glidants (e.g.,
flavorings, sweeteners, and miscellaneous materials such as buffers and adsorbents.
- Explain how hydrophilic polymers contribute to the sustained release of amphetamine from the conjugate in the stomach and intestines.
Hydrophilic polymers gel and dissolve slowly in aqueous acidic media in the stomach, allowing the amphetamine conjugate to diffuse from the gel. When the gel reaches the intestines, it dissolves in controlled quantities in the higher pH medium, allowing further sustained release.
- What are some examples of water-insoluble hydrophobic substances used to delay the release of water-soluble vitamins?
Examples of water-insoluble hydrophobic substances used to delay the release of water-soluble vitamins include diethyl phthalate, diethyl sebacate, and castor oil.
- What is the purpose of using hydrophilic plasticizers when water- insoluble vitamins are employed?
Hydrophilic plasticizers are used to aid in dissolving the encapsulated film, creating channels on the surface, which facilitates the release of the nutritional composition.
- Name three types of release mechanisms that can be combined in a dosage form.
The dosage form can combine immediate release, extended release, and delayed release mechanisms.
- What are some examples of binding agents that can be used in pharmaceutical formulations?
Examples of binding agents include starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, and polyvinylpyrrolidone.
- Describe how the dose range for adult human beings is determined, according to the text.
The dose range for adult human beings depends on a number of factors including the age, weight, and condition of the patient.
- Explain how covalently binding amphetamine to a chemical moiety can reduce its potential for abuse.
Covalently binding amphetamine to a chemical moiety can reduce its potential for abuse by reducing the rate of absorption, increasing the rate of clearance of pharmacologically active amphetamine, and preventing spiking or increased blood serum concentrations compared to unbound amphetamine when given at doses exceeding those within the therapeutic range.
- What are some examples of medically inert ingredients that can be included in pharmaceutical formulations?
Examples of medically inert ingredients include solid and liquid diluents such as lactose, dextrose, saccharose, cellulose, starch, or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules, and water or vegetable oil for suspensions or emulsions.
- According to the text, what are some potential benefits of covalently binding amphetamine to a chemical moiety?
According to the text, potential benefits include substantially lower toxicity compared to unbound amphetamine, reduced or eliminated possibility of overdose by oral or intranasal administration, and a steady-state serum release curve that provides therapeutic bioavailability while preventing spiking.
- Explain how the invention aims to alter amphetamines to decrease their potential for abuse, focusing on the mechanism of action related to bioavailability.
The invention aims to decrease the abuse potential of amphetamines by covalently attaching them to chemical moieties. This attachment is designed to modify the bioavailability of the drug. Specifically, the goal is to maintain a therapeutically effective bioavailability while preventing the rapid increase in blood serum concentrations (spiking) that is characteristic of unbound amphetamine, especially when taken in excessive doses. This is achieved by controlling the rate of absorption and/or clearance of the drug, thus reducing the euphoric effects associated with rapid drug delivery and making it less attractive for abuse.
- Describe a scenario where the solubility and dissolution rate of the composition is substantially changed under physiological conditions, and explain the potential impact on bioavailability.
The solubility and dissolution rate of the composition can be substantially changed under physiological conditions encountered in the intestine, at mucosal surfaces, or in the bloodstream. In one embodiment, the solubility and dissolution rate substantially decrease the bioavailability of the amphetamine, particularly at doses above those intended for therapy. This could be achieved by designing the chemical moiety to be less soluble in the specific pH or enzymatic environment of the intestine, thus limiting the amount of amphetamine that is released and absorbed into the bloodstream. This reduced bioavailability at higher doses helps to prevent overdose and abuse.
- What is the primary purpose of covalently attaching a chemical moiety to amphetamine, according to the text?
The primary purpose is to decrease the pharmacological activity of amphetamine when the composition is used in a manner inconsistent with the manufacturer's instructions, reduce the potential for overdose, and reduce or prevent the euphoric effect.
The amphetamine composition provides a therapeutically bioequivalent AUC (area under the curve) when compared to amphetamine alone but does provide a lower Cmax, which results in reduced euphoria.
- Describe the deprotection step in the synthesis of L-lysine-d- amphetamine and explain its purpose.
The deprotection step involves dissolving the protected amide (Boc- Lys(Boc)-Amp) in anhydrous dioxane and adding 4M HCl/dioxane. This removes the Boc (tert-butoxycarbonyl) protecting groups from the lysine amino groups, yielding the free amine salt of the L-lysine-d-amphetamine conjugate. The purpose of this step is to obtain the final, deprotected L- lysine-d-amphetamine product, which is the active form of the conjugate.
- Explain how the methods described in the text could be used to treat ADHD, ADD and narcolepsy.
The text describes methods of treating ADHD, ADD and narcolepsy by administering compounds or compositions of the invention, where amphetamine is covalently bound to a chemical moiety. This approach aims to provide a controlled release of amphetamine, reducing the potential for abuse and overdose while still delivering the therapeutic benefits of the drug for these conditions. The slower release and lower Cmax are intended to minimize the euphoric effects associated with amphetamine, making it a safer option for long-term treatment.
- What is the effect of conjugating lysine to d-amphetamine on peak amphetamine levels?
Conjugating lysine to d-amphetamine decreases the peak levels of amphetamine.
- According to Example 6, how does the bioavailability of amphetamine released from L-lysine-d-amphetamine compare to that of amphetamine sulfate at an equivalent dose?
The bioavailability of amphetamine released from L-lysine-d-amphetamine is similar to that of amphetamine sulfate at the equivalent dose.
- What observation was made regarding the release of amphetamine from L-lysine-d-amphetamine?
A gradual release of amphetamine from L-lysine-d-amphetamine was observed.
- Based on the data provided, what is the primary benefit of the gradual release of amphetamine from L-lysine-d-amphetamine?
The gradual release of amphetamine from L-lysine-d-amphetamine and decrease in peak levels reduce the possibility of overdose.
- How does the time to peak concentration (Tmax) of L-lysine-d- amphetamine compare to that of d-amphetamine?
The time to peak concentration for L-lysine-d-amphetamine was similar to that of d-amphetamine.
- According to the text, what happens to the levels of d- amphetamine at 30 minutes post-administration when lysine is conjugated to d-amphetamine over a dose range of 1.5 to 12 mg/kg?
The levels of d-amphetamine at 30 minutes post-administration are decreased by approximately 50% when lysine is conjugated to d- amphetamine over a dose range of 1.5 to 12 mg/kg.
- At a suprapharmacological dose (60 mg/kg), how do the levels of d-amphetamine from L-lysine-d-amphetamine compare to those seen for d-amphetamine sulfate at 0.5 hours post-dosing?
At a suprapharmacological dose (60 mg/kg), the levels of d-amphetamine from L-lysine-d-amphetamine only reached 8% of those seen for d- amphetamine sulfate.
- Explain how L-lysine-d-amphetamine reduces the abuse potential compared to d-amphetamine sulfate, based on the provided information.
L-lysine-d-amphetamine reduces abuse potential because, at high doses (e.g., 60 mg/kg), the oral bioavailability of d-amphetamine is substantially decreased compared to d-amphetamine sulfate. This means that even if a large dose is taken, the amount of d-amphetamine that reaches the bloodstream is significantly lower, reducing the euphoric effects and thus the potential for abuse. The slower release also contributes to this effect.
- Based on Example 10, how does the Cmax and AUC of d- amphetamine following administration of L-lysine-d-amphetamine compare to that of intact extended-release d-amphetamine sulfate capsules?
The Cmax and AUC of d-amphetamine following administration of L-lysine-d- amphetamine were similar to that of the intact extended-release capsule.
- Explain the difference in d-amphetamine release between crushed extended-release capsules and L-lysine-d-amphetamine, and why this difference is significant.
Crushing extended-release capsules increases both Cmax and AUC of d- amphetamine, circumventing the extended-release mechanism. However, L- lysine-d-amphetamine maintains its extended-release properties even if manipulated, as the extended release is inherent to the compound itself. This is significant because it makes L-lysine-d-amphetamine less susceptible to abuse by methods like crushing, which can lead to a rapid and potentially dangerous release of d-amphetamine from traditional extended-release formulations.
