Methamphetamine structure activity relationship of salicylates

Methamphetamine | Podcast | Chemistry World

An approach started from methyl salicylate is outlined in Scheme [16,17]. .. Structure–activity relationships cocaine, and methamphetamine, effects blocked by α1-antagonists, further supporting activity of atomoxetine at the . Methamphetamine Abuse and Related Problems: sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, and alkyl glycosides. 1A- 1D), and a diagram and table of structure-activity relationships. Acne Solutions Liquid Makeup Salicylic Acid Acne Treatment, Liquid, mL/ Salicylic acid may decrease the excretion rate of Methamphetamine which inducers, inhibitors and structure-activity relationships of human Cytochrome.

Over in the US that same year, the 'Summer of Love' in the Haight-Ashbury region of San Francisco was fuelled by marijuana and psychedelics like LSD, but the following year things went badly wrong with a wave of intravenous methamphetamine injection. The motto changed from 'peace and love' to 'speed kills.

This has the effect of stimulating regions of the brain linked with vigilance and the action of the heart, so that the blood pressure and heart rate go up. Amphetamines alleviate fatigue and make the user feel stronger, euphoric and more alert.

Most drugs of abuse like cocaine and heroin are plant-based, and can be intercepted at national borders, but methamphetamine is a synthetic drug.

One reason that amphetamine abuse is widespread in countries like the US is that methamphetamine can easily be synthesised, not just in laboratories, but also in trailer parks, motel rooms and ranches. Cookbook instructions are readily available on the internet. Two methods that have been described involve the reduction of ephedrine itself readily available from over-the-counter cough remedies with either lithium in liquid ammonia, or else red phosphorus and iodine as the reducing agents.

If methamphetamine hydrochloride is recrystallised carefully, you can get large crystals that have become known as 'crystal meth' or 'ice'. These can be smoked rather than injected, which has also contributed to increases in methamphetamine abuse.

Because of the energy rush they give, sportsmen used amphetamines long before they turned to steroids, and they were banned from the Olympics in He was the first Briton, ever, to win a medal in alpine skiing, but within a few days a urine test detected traces of methamphetamine, and he lost his medal. Baxter had had nasal congestion for years, and used British Vicks nasal inhalers to relieve the symptoms; they contain chemicals like menthol, camphor and methyl salicylate which shrink inflamed membranes.

He saw a Vicks inhaler in a shop that looked just like the ones he used in the UK, so he bought it. American Vicks contains some different compounds to British Vicks, one of those is laevo-methamphetamine. L-methamphetamine is simply a decongestant, and has little stimulant activity, unlike its optical isomer, dextro-methamphetamine.

Sadly, the International Olympic Committee regulations make no distinction between the isomers. In a way, Baxter was fortunate - he only lost a medal. On stage 13 on 13 July, he died from a heart attack while climbing Mont Ventoux. His death was brought on a by a combination of intense heat, some brandy he'd drunk, and Tonedron - a form of methamphetamine.

People argue about the dangers of taking methamphetamine. But in Tom Simpson's case, speed killed. Never miss a podcast again! Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, such as preservatives.

The therapeutic agents of the invention e. The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients.

If the active compound is substantially insoluble, it can be milled to a particle size of less than mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e. Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.

The formulations can additionally include: Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al. The pharmaceutical compositions can be formulated so as to provide immediate, extended, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosage containing, e. For example, the dosages can contain from about 0.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with one or more pharmaceutical excipients to form a solid bulk formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these bulk formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets and capsules.

This solid bulk formulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0. Compositions for Oral Administration.

Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient s in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers e.

Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent e. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.

Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration vs time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e. Thus, the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner.

Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. In a controlled release matrix formulation, the matrix material may also include, e. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions suitable for oral mucosal administration e. The pharmaceutical compositions formulated for oral delivery, such as tablets or capsules of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of delayed or extended release. The coating may be adapted to release the active drug substance in a predetermined pattern e. Exemplary enteric coatings that can be used in the pharmaceutical compositions described herein include sugar coatings, film coatings e.

Furthermore, a time delay material such as, for example, glyceryl monostearate or glyceryl distearate, may be employed. For example, the tablet or capsule can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.

The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. When an enteric coating is used, desirably, a substantial amount of the drug is released in the lower gastrointestinal tract.

In addition to coatings that effect delayed or extended release, the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes e.

The coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, vols. Swarbrick and Boyland, Within the scope of the present invention are also parenteral depot systems from biodegradable polymers. These systems are injected or implanted into the muscle or subcutaneous tissue and release the incorporated drug over extended periods of time, ranging from several days to several months.

Both the characteristics of the polymer and the structure of the device can control the release kinetics which can be either continuous or pulsatile. Polymer-based parenteral depot systems can be classified as implants or microparticles.

Extrusion, compression or injection molding are used to manufacture implants whereas for microparticles, the phase separation method, the spray-drying technique and the water-in-oil-in-water emulsion techniques are frequently employed.

Of particular interest are in situ forming depot systems, such as thermoplastic pastes and gelling systems formed by solidification, by cooling, or due to the sol-gel transition, cross-linking systems and organogels formed by amphiphilic lipids. Examples of thermosensitive polymers used in the aforementioned systems include, N-isopropylacrylamide, poloxamers ethylene oxide and propylene oxide block copolymers, such as poloxamer andpoly N-vinyl caprolactampoly siloethylene glycolpolyphosphazenes derivatives and PLGA-PEG-PLGA.

Mucosal drug delivery e. Methods for oral mucosal drug delivery include sublingual administration via mucosal membranes lining the floor of the mouthbuccal administration via mucosal membranes lining the cheeksand local delivery Harris et al.

For buccal administration, the compositions may take the form of, e. Permeation enhancers can also be used in buccal drug delivery. Exemplary enhancers include lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, lysophosphatidylcholine, methol, methoxysalicylate, methyloleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, and alkyl glycosides.

methamphetamine hydrochloride drugs: Topics by

Bioadhesive polymers have extensively been employed in buccal drug delivery systems and include cyanoacrylate, polyacrylic acid, hydroxypropyl methylcellulose, and poly methacrylate polymers, as well as hyaluronic acid and chitosan. Liquid drug formulations e. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art.

Formulations for sublingual administration can also be used, including powders and aerosol formulations. Exemplary formulations include rapidly disintegrating tablets and liquid-filled soft gelatin capsules. The amount and frequency of administration of the compositions can vary depending on, for example, what is being administered, the state of the patient, and the manner of administration.

The dosage is likely to depend on such variables as the type and extent of progression of the methamphetamine addiction, HIV infection, or neuroinflammation, the severity of the medical and behavioral consequences of methamphetamine use and HIV infection, or neuroinflammation, the age, weight and general condition of the particular patient, the relative biological efficacy of the composition selected, formulation of the excipient, the route of administration, and the judgment of the attending clinician.

Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test system. An effective dose is a dose that produces a desirable clinical outcome by, for example, improving a sign or symptom of chronic tissue ischemia or slowing its progression.

The amount of TSPO compound per dose can vary. For example, a subject can receive from about 0. Exemplary dosage amounts can fall between 0. Exemplary dosages can 0. In another embodiment, the administered dosage can range from 0. The frequency of treatment may also vary. The subject can be treated one or more times per day with a TSPO compound e.

Preferably, the pharmaceutical composition is administered 1 or 2 times per 24 hours. The time course of treatment may be of varying duration, e.

For example, the treatment can be twice a day for three days, twice a day for seven days, twice a day for ten days. Treatment cycles can be repeated at intervals, for example weekly, bimonthly or monthly, which are separated by periods in which no treatment is given.

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The treatment can be a single treatment or can last as long as the life span of the subject e. Any of the pharmaceutical compositions of the invention described herein can be used together with a set of instructions, i. The kit may include instructions for use of the pharmaceutical compositions as a therapy as described herein. For example, the instructions may provide dosing and therapeutic regimes for use of the compounds of the invention to reduce incidence, duration, and or severity of methamphetamine addiction, medical and behavioral consequences of methamphetamine use and HIV infection, or neuroinflammation.

Various objects, features, aspects, and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components.

The present invention may address one or more of the problems and deficiencies of the current technology discussed above. However, it is contemplated that the invention may prove useful in addressing other problems and deficiencies in a number of technical areas. Therefore the claimed invention should not necessarily be construed as limited to addressing any of the particular problems or deficiencies discussed herein.

It is to be appreciated that the accompanying drawings are not necessarily to scale since the emphasis is instead placed on illustrating the principles of the invention. The invention will now be described, by way of example, with reference to the accompanying drawings in which: It is to be appreciated that the following detailed description of various embodiments is by way of example only and is not meant to limit, in any way, the scope of the present invention.

In the summary above, in the following detailed description, in the claims below, and in the accompanying drawings, reference is made to particular features including method steps of the present invention.

It is to be understood that the disclosure of the invention in this specification includes all possible combinations of such particular features, not just those explicitly described. Where reference is made herein to a method comprising two or more defined steps, the defined steps can be carried out in any order or simultaneously except where the context excludes that possibilityand the method can include one or more other steps which are carried out before any of the defined steps, between two of the defined steps, or after all the defined steps except where the context excludes that possibility.

For example, 25 to mm means a range whose lower limit is 25 mm, and whose upper limit is mm. The embodiments set forth the below represent the necessary information to enable those skilled in the art to practice the invention and illustrate the best mode of practicing the invention.

In addition, the invention does not require that all the advantageous features and all the advantages need to be incorporated into every embodiment of the invention. Turning now to FIGS. Benzodiazepines and Psychostimulant Abuse: By increasing the affinity of GABA for the receptor, benzodiazepine agonists increase the frequency of channel opening and facilitate the influx of chloride ions, resulting in a hyperpolarization of the membrane and decreased action potential propagation.

This classical mechanism of action applies to nearly all benzodiazepines, including alprazolam and oxazepam. However, some benzodiazepines also have a high affinity for a second binding site, formerly known as the peripheral benzodiazepine receptor. Importantly, many benzodiazepines, most notably diazepam and midazolam, bind to and activate the TSPO to increase neurosteroid biosynthesis. The TSPO is responsible for catalyzing the first steps of steroidogenesis by translocating cholesterol from the cytoplasm into the mitochondrial matrix.

This allows cholesterol side-chain cleavage enzyme CYP11A1; also known as Pscc to convert cholesterol to pregnenolone, the first enzymatic conversion in the steroid biosynthesis cascade. As shown in FIG. Subsequent ex vivo homogenate binding assays have confirmed the inventors' hypothesis in rat brain tissue. Benzodiazepines Affect Cocaine and Methamphetamine-Related Behaviors Differently— The inventors' laboratory has long been interested in the role for benzodiazepines in drug addiction.

Early research demonstrated that chronic cocaine exposure differentially affects the density of benzodiazepine receptors across several brain regions, an effect that is dependent on intact dopaminergic signaling. Additional research showed that several benzodiazepine receptor agonists could decrease cocaine related behaviors, including chlordiazepoxide, alprazolam, and oxazepam.

However, evidence from the inventors' laboratory demonstrated that oxazepam and alprazolam differentially affect the discriminative stimulus effects of cocaine and methamphetamine in female rats. As shown in FIGS. However, pretreatment with oxazepam dose-dependently decreased the discriminative stimulus effects of both cocaine and methamphetamine. These results were supported by additional findings from the inventors' laboratory whereby oxazepam and alprazolam altered cocaine and methamphetamine self-administration in remarkably different ways.

In male rats trained to self-administer methamphetamine 0. On the other hand, as shown in FIG. These observations have been confirmed using a conditioned place preference model as well, evidencing that benzodiazepines differentially modulate the rewarding and reinforcing properties of methamphetamine.

These data were further supported by a drug-induced reinstatement D-IR study. Thus, this is an extraordinarily consistent pattern across three very different models of drug-related behaviors. On the other hand, both oxazepam and alprazolam reduce cocaine-related behaviors in a similar manner. The inventors conclude, based on such evidence, that the different effects between oxazepam and alprazolam stem from their differential binding to GABAA receptors and to the TSPO, and that these differences especially impact their actions on methamphetamine pharmacology.

Some effects of oxazepam and alprazolam on the subjective effects of d-amphetamine and methamphetamine have previously been reported, which at first blush appear to contradict the inventors finding. The differences between those results in humans and the inventors' data in rats are likely a result of the doses used as well as the differences in pharmacokinetics due to the route of administration.

For example, significant differences are observed in the time to maximum methamphetamine concentrations in the blood Tmax of humans when comparing intravenously administered methamphetamine i.

In contrast, the Tmax for intraperitoneal methamphetamine injections in rats is 7. Methamphetamine or d-amphetamine was administered intra-nasally or orally in the human studies, suggesting that Tmax would not have been reached in the Rush experiments as it was in the inventors' rat studies. In addition, in the Rush experiments the benzodiazepines were administered acutely at the same time as amphetamine, and oxazepam may not have had sufficient time to reach maximum blood levels as it is more slowly absorbed compared to alprazolam.

Finally, the doses of d-amphetamine or methamphetamine tested in the human studies i. Intravenous methamphetamine users are known to inject doses as high as mg at a time. Thus, the lack of reproducibility between the inventors' studies and those Rush conducted in humans are likely due to factors e.

The inventors are aware that oxazepam is one of the least desirable benzodiazepines by drug-dependent individuals. In contrast, alprazolam is consistently related as one of the most desired benzodiazepines by drug-dependent individuals.

Methamphetamine-induced neurotoxicity: structure activity relationships.

This difference between oxazepam and alprazolam is one of the reasons that the inventors have recently focused on oxazepam for its potential in treating drug-dependent subjects.

The inventors conclude, based on the experimental evidence, that the differences in abuse liability between oxazepam and alprazolam stem from their differential interactions with GABAA receptors and the TSPO. Such experiments include those to assess the receptors potentially responsible for the effects of oxazepam and alprazolam on methamphetamine self-administration in rats.