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a-PVP

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Alpha-Pyrrolidinopentiophenon (α-PVP, alpha-PVP, flakka, speed, fk, F, crystal love, gravel, pure NRG, vanilla sky, snow Blow) is a highly active synthetic psychostimulant, categorized as an actinone. It is presented as a chemical substance of desmethyl pyrrovaleron, which is fundamentally close to an alkaloid catha edulis. α-PVP is one of the most powerful psychostimulants, several times more powerful both in terms of clinical effects in equivalent doses, and in the severity of side effects in comparison with any other psychoactive substance in its class. The name of the substance using chemical classification is - (RS)-1-Phenyl-2-(1-pyrrolidinyl)-1-pentanone. The substance has a molecular formula C15H21NO and most often it is presented in the form of hydrochloride salt, a colorless crystal that melts at a temperature of 162-173 degrees Celsius. As a rule, the substance on the market can have any kind, color and consistency. So, on the market you can see this substance in the form of a crystal of white (cloudy), beige, blue, green, red, cream colors, in the form of flour. The substance is moderately well soluble in water and other organic solvents (for example, methanol, ethanol). The substance has a high lipophilicity (due to the replacement of the amino group with a pyrrolidine ring), which is one of the criteria for increasing permeability through the blood-brain barrier.

Formula


Pharmacokinetics.
A lot of metabolites of α-PVP are described. The metabolism begins with the hydroxylation of the side chain, the pyrrolidine and benzene rings, the reduction of the ketone group, the oxidation of the alkyl chain and the oxidation of the pyrrolidine cycle to the corresponding lactam, the opening and decomposition of the pyrrolidine ring to the primary amine. In rats, it turns into a primary amine due to the destruction of the pyrrolidine ring, whereas in humans this pathway additionally includes the restoration of the ketone group to hydroxy- α – PVP. Reduction and hydroxylation of α-PVP is also accompanied by formation of N-(1-hydroxy-1- phenylpentan-2-yl)pyrrolidin-2-ol, which is not detected during in vivo studies. Moreover, α-PVP undergoes hydroxylation of the carbon atom of the penultimate side chain to form 4-hydroxy- α-PVP with its subsequent hydroxylation of the pyrrolidine ring, oxidation and opening of the ring with additional oxidation. Distribution of α-PVP and its metabolites occurs in almost all organs in different concentrations, however, there is no data on its distribution in adipose tissue, although it is a relatively lipophilic compound. α-PVP concentration in blood varies from trace amounts to 6.2 micrograms/ml (a lethal concentration).

Metabolism


The volume of distribution is about 1.4-1.8 l/kg, the highest bioavailability with the inhalation administration is 85-90%, about 60% of α-PVP is binded to plasma protein. In blood, the lethal concentration for a person is 920 ng/ml. Metabolites of α-PVP don't remain in hair for a long time, which is a useful tool for forensic diagnostics. Lethal dose of α-PVP with oral administration according to various sources, varies from 240 to 280 mg/kg, with intravenous administration - 70-120 mg/kg. Cytochrome p450 enzymes that predominantly affect α-PVP metabolism are CYP2D6, CYP2C19, CYP1A244. The dissociation constant is 17.90664. α-PVP elimination half-life is about 4.33 hours. However, according to some authors, in studies on humans, the half-life for the second half-period after injection was found to be about 40 hours. In the brain, the concentration after the initial distribution is several times greater than in plasma.

Pharmacodynamics.
α-PVP, like most psychostimulants, is a powerful inhibitor of catecholamine uptake due to the inhibition of DAT and NAT, while, at the same time, it is a weak inhibitor of the serotonin transporter. Partially and indirectly, α-PVP has the property of activating D1 and D2 receptors. IC50 of α-PVP varies in the range from 12.8 to 205 nM for DAT, 4.2-20 nM for NET and 10-30 nM for SERT. The predominant increase in the extracellular concentration of dopamine occurs in the striatum, compared to other parts of the brain. There are proven statistically significant conclusions that pyrrovalerones have direct myotoxicity, which is caused by an increase in concentrations of superoxide radical anions and a decrease in normal adapted cellular respiration that disrupt the integrity of the cell membrane of myoblasts. As for α-PVP enantiomers, in the racemate, the left-sided enantiomer is more effective (by dozens of times) than its symmetrical right-sided form. In the context of research about α-PVP activity on trace amino-bound receptor of type 1, it was revealed that the substance has minimal activity on this class of protein, so we can say that pyrrovaleron is an incomplete agonist of TAAR1, but the effect on the vesicular transporter of type 2 monoamines is quite strong, compared to, e.g., amphetamines.

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Signs and symptoms related to a-PVP administration:
Insomnia (can last several days), anxiety, convulsions, seizures, myoclonus, mydriasis, dysarthria, nystagmus, dizziness, syncope, headache, vertigo, loss of consciousness, cognitive deficits, confusion, memory loss.
Psychomotor.
Agitation, self-injury, combative, aggressive and bizarre behavior, disorientation, excited delirium, irritability, fatigue, restlessness, tremor, hallucinations, muscle spasms, paranoia, psychosis, dysphoria, delusions.
Cardiovascular system
Hypertension, tachycardia, diaphoresis, thoracalgia, cardiac arrest and dysrhythmias, cerebral infarction, ST-elevation.
Respiratory system.
Dyspnea and pulmonary edema.
Gastrointestinal
Nausea, vomiting
Hematological.
Leukocytosis, disseminated intravascular coagulation.
Miscellaneous effects.
Panic attacks, irritation burns (if vaporized), suicidal ideation, craving, distorted perceptions, bruxism, motivation suppression, anorexia, rhabdomyolysis, hyperthermia, acute kidney and liver failure, dehydration, diaphoresis, multiorgan failure.
Contraindications and precautions.
Elderly, hypovolemic, hypotensive and patients with impaired cardiac function.
Clinical chemistry results.
Increase in creatine, creatine kinase, creatinine, myoglobin, AST, ALT, procalcitonin, PT-INR, troponin I, hyponatremia, hypokalemia, hypoglycemia, respiratory alkalosis, metabolic acidosis.
The effect of stimulation while using α-PVP is allegedly one of the most powerful among psychostimulants more or less available in the world. It is characterized by stereotypical repetitive movements, agitation, up to uncontrolled movements. “Body high” is one of the predominant effects in the first dozen of minutes after use, and it is usually long-lasting. The cardiac rhythm disturbance that occurs during use may persist for 15-30 hours after use, single extrasystoles or transient atrial fibrillation may be recorded during ECG studies. Decreased appetite, "vibrating vision", "restless legs' syndrome", bruxism, just as while using other psychostimulants, are transient, they are not regular accompanying effects of α-PVP use.

Also, the effects include various illusions, which are especially pronounced during the peak of action of the substance. So, 10-20 minutes after intravenous injection of α-PVP, "Peripheral information misinterpretation" and “Scenarios and plots”, "auditory hallucinations and distortions", decreased visual acuity with spasm of accommodation can be present during the trip and cause anxiety. Cases of complete loss of vision are described, which often correlates with a stroke on the background of psychostimulant overdose.

In 2019, Newoki studies identified and proved cognitive depression, chronic fatigue syndrome, sleep-wake cycle disorder, anxiety disorder, a pronounced decrease in motivational activity; these disorders can persist for one year after α-PVP deprivation, and require correction by psychotherapist and pharmacological treatment. With clinical approach, anxiety and paranoia are among the predictive factors of identification of α-PVP use. Retrograde studies revealed a direct correlation between paranoia occurrence and perrovaleron use.

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The studies of Valen and Karila prove the fact of both direct and indirect damage to elements of the central nervous system and neurotoxicity. Organic and irreversible brain damage can occur after 1 year of systematic α-PVP use when used no less than 2 times a week. The long-term consequences are unknown, but short-term in vivo studies revealed a pronounced decrease in "neural connections" with predominance of amyloid in some parts of the brain and decrease in cognitive abilities according to the results of testing. Changes in the cardiovascular system appear after 2 months of systematic use with a predominance of constant spasm and dysfunction of the vessels of the microcirculatory bed, which is clinically manifested as "sensations of cold limbs", periodic discomfort in the chest area, "tingling" in the extremities. The morphological substrate of the changes is the predominance of zones of functional concentric hypertrophy, zones of myocardial ischemia, thickening of the heart valves walls, the appearance of vegetation on them, all of these are the results of pyrrovaleron pro-inflammatory effects. The most critical pathognomonic symptom of α-PVP overdose is stimulant psychosis, which occurs with rather high frequency compared with the other psychostimulants. It is characterized mainly by complete disorientation in space and time, often unmotivated aggression, rash actions, up to self-mutilation and attacks on other people (absolute affective state). In such cases, treatment is carried out exclusively by strong antipsychotics, with mandatory monitoring of the patient during the day in a hospital.

Methods of use and doses.
α-PVP is frequently used with the help of "foil", when a suspended substance is poured on the foil and subjected to high-thermal treatment until it turns into “liquid sediment”. Then the vapour is inhaled either through glass tubes or so-called "light bulbs". In this case, the effect occurs instantly and is characterized as pronounced, but not long-lasting. The peak comes after 20-40 minutes, with a short plateau and the onset of post-effects. The least dangerous method is smoking through glass tubes, which must be regularly maintained, cleaned and treated with solutions. Light dose with this administration is 0.02 – 0.08 mg/kg, medium dose is about 0.21 mg/kg, high doses are from 0.30 mg/kg and more.

The most common method of administration among chronic users is intravenous injection. The high is the most powerful and the quickest out of all methods, but the effect lasts less, there appears a need to give injections with increasing frequency. That is why intravenous use is the quickest way to addiction. Moreover, the danger of use is in getting the product diluted with unknown components from the street suppliers. These components get directly into the bloodstream, past the liver filter. Little experience of intravenous use, violation of hygiene rules, piercing of a vein, by-products of synthesis and additives – these are aspects that need consideration. Medium dose with this method is 0,05-0,1 mg/kg, sometimes with a present chronic pyrrovaleron intoxication and long-term use doses can vary from 0,2-0,8 mg/kg.

Intranasal administration is classic, but not the method of choice, and it implies the standard consequent complications and undesirable phenomena in the form of chronic damage to the mucous membrane, chronic rhinitis, rhinosinusitis, possible sinusitis and the chance of perforation of the walls of the nasal passages. Medium dose with intranasal administration is 0,15-0,25 mg/kg.

It is a very rare occurrence, when α-PVP is used orally, diluted in water or taken in gelatin capsules by the "bomb" method. This method has the lowest bioavailability, the minimum effect. Medium doses, as a rule, are around 0.8-1.4mg/kg, which negates the point of the act of using this way.

Complications associated with cocaine use.
The most common symptoms of overdose are the following:
1. Intense headache (localized or non-localized, often pulsating) that occurs 10-30 minutes after use and lasts more than half an hour, often accompanied by nausea and vomiting.
2. Sternum pain, discomfort in the left hypochondrium, chest area on the left, irradiation of pain to the left, in the left upper limb, left clavicle, decreased superficial sensation in the left parts.
3. Panic attacks, psychosis, anxiety, depersonalization/derealization.
4. An increase in the pulse rate of more than 110 per minute, an increase in blood pressure of more than 140/95 mmHg.
5. An increase in body temperature of more than 37.5 C and hyperthermia lasting more than one hour after use.
6. Fine tremor, convulsions, impaired consciousness up to a coma.
7. Acute coronary syndrome.
8. Sudden cardiac death.
9. Serotonin syndrome.

First aid for overdose
Indications for going to the hospital or calling an ambulance: impaired or absent consciousness, impaired speech, motor activity, lack of orientation in space and time, severe pain behind the sternum lasting more than half an hour, an increase in body temperature of more than 38.0 C or hyperthermia lasting more than half an hour, an increase in blood pressure of more than 180/110 mmHg with no effect of hypotensive therapy.
1. The treatment of patients with blood pressure of more than 140/95 mm Hg includes one tablet of a beta-blocker without intrinsic sympathomimetic activity, one tablet of an ACE inhibitor, after 30 minutes - one tablet of a tranquilizer (0.25 mg of alprazolam).
2. In patients with intense anxiety, panic attack, psychosis: one tablet of a tranquilizer and one tablet of a neuroleptic with a sedative effect, psychological help, emergency psychotherapy.
3. In patients with sternum pain, discomfort in the chest: one tablet of slow calcium channel blockers of the third generation, reflexively reducing the heart rate, one tablet of an ACE inhibitor of the 3rd generation OR one tablet of an agonist of imidazoline effects OR one tablet ; if the pain syndrome does not become less intense within 20 minutes, then it is recommended to go to the hospital.
4. When there is an increase in body temperature of no more than 37.5 C, dynamic observation for half an hour is ordered. Pharmacological treatment is not required. If hyperthermia persists for more than half of an hour (in the absence of external causes), then it is recommended to go to the hospital.
5. In patients with intense headaches, it is recommended to use antispasmodics in combination with sedative herbal remedies or tranquilizers in low doses. If the headache is associated with vomiting, an intramuscular injection of metoclopramide 2.0 ml is recommended. Isolated nausea and functional dyspepsia do not require pharmacological treatment.
6. For tremors, moderate convulsions or mild psychomotor agitation, tranquilizers are recommended. It is strongly advised not to use neuroleptics in these cases.

Methods of reducing harm caused by α-PVP use.
When injecting, be sure to use only disposable syringes and sterile supplies. Treat your hands and the injection site with an antiseptic solution three times. After the injection, do not forget to repeat the treatment. If the solution gets past the vein, it is necessary to apply a semi-alcoholic compress (30% alcohol and 70% sodium chloride solution at a concentration of 0.9%) for 1 hour, and then apply a 2 mm layer of heparin-containing cream for 12 hours.

After use, it is advisable to monitor blood pressure, pulse and body temperature every hour. It is absolutely necessary to restore the water-electrolyte balance. For this purpose, chloride-bicarbonate-sodium water is used in a volume of about three liters within 24 hours. If it is impossible to empty the bladder, it is recommended to take a warm bath, drink an antispasmodic agent. For preventive purposes, 24 hours before the act of use, it is necessary to start taking a course of proton pump inhibitors, magnesium preparations (preferably combination of asparaginate and orotate), ascorbic acid at a dose of 500 mg per day and continue taking these drugs for at least 5 days after the act of use.

Intranasal use is always associated with damage to the mucous membranes. To reduce the risks of developing consequences, it is necessary to wash the nose with a slightly saturated saline solution every 30 minutes for preventive purposes, perform respiratory exercises with acts of forced exhalation, use herbal preparations that include such components as yellow gentian, spring primrose, acetosa, sorrel, black elderberry, verbena officinalis.

Risk of serotonin syndrome development with α-PVP use is incredibly high compared with other psychostimulants due to the specificity of its action and the special way of passing through the blood-brain barrier. The highest probability of its manifestation is within 12 hours since pyrrovaleron use. As a rule, in case of a mild course of serotonin syndrome, sedatives of benzodiazepine group and b-blockers are effective.
 
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