#also posting this after a cannabis induced psychotic episode

[spro-o]

Drag kings Cameron and Thirteen 🙏🙏

ugh ur so right, king - the patient needs even more PPTH doctors in drag ❤️

as always, go crazy with the name suggestions

[juniperpublishersanatomy-blog]

Alleviation of Acute Poisoning of Organophosphates in Humans-Juniper Publishers

Organophosphates (OPs) are used as pesticides and developed as warfare nerve agents. Exposure to an organophosphate could be lethal resulting in death due to respiratory failure. The mechanism of organophosphate poisoning includes inhibition of the acetyl cholinesterase (AChE) via phosphorylation of the hydroxyl group of serine present at the active site of the enzyme. The inhibition of acetyl cholinesterase (AChE) results in the accumulation of acetylcholine (ACh) at cholinergic receptor sites, producing continuous stimulation throughout the nervous systems. Several therapeutic agents have been developed and used in the treatment of poisoning with OPs. For example, pyridiniumoximes have been developed as therapeutic agents for the treatment of poisoning by OPs. The mode of action of pyridiniumoximes is by the reactivation of inhibited acetyl cholinesterase. However, the universal broad spectrum oximes capable of protecting against all known OPs, is still have to be investigated. Presently, a combination of an antimuscarinic agent, e.g. atropine, an AChE reactivators i.e. oximes and diazepam are used for the treatment of organophosphate poisoning in humans. In spite of enormous efforts devoted to the development of new AChEreactivators as antidotes against poisoning with organophosphates, only four compounds so far have been found their applications in human medicine. This article presents an updated account of the available reports concerning the treatment of OP poisoning and its alleviation. Keywords:  Pesticides; Organophosphate Poisoning; Antidote; Acetyl cholinesterase; Cholinergic; Alleviation

Abbreviations:  OP: Organophosphate; AChE: Acetylcholinesterase; ChE: Cholinesterases; Ach: acetylcholin

Introduction

Acetylcholinesterase (AChE) (EC 3.1.1.7) is the primary cholinesterase belongs to carboxylesterase family . It is an acetylhydrolase, found in many types of conducting tissues. AChE is also found on the red blood cell membranes and blood plasma (EC 3.1.1.8, ChE) [1]. The function of AChE is the termination of ACh at the junctions of the various cholinergic nerve endings with their post-synaptic sites which catalyzes the breakdown of acetylcholine that function as neurotransmitters with very high catalytic activity. The turn over number for AChE has been found to be about 25000 molecules of acetylcholine (ACh) hydrolysed per second [2]. The AChE activity is higher in motor neurons than in sensory neurons [3,4]. AChE exists in multiple molecular forms with different oligomeric assembly but having the same catalytic activities. The enzyme has been reported to be membrane bound [5-7]. The active site of AChE has two sub sites - anionic site and esteraticsubsite. The esteraticsubsite contains the catalytic triad of three amino acids: serine 200, histidine 440 and glutamate 327 similar to the triad in other serine proteases except that the glutamate is the third member rather than aspartate, where acetylcholine is hydrolyzed to acetate and choline [8]. The hydrolysis reaction of the carboxyl ester forms an acyl-enzyme and free choline. Then, the acyl-enzyme undergoes nucleophilic attack by a water molecule, assisted by the histidine 440 group, liberating acetic acid and regenerating the free enzyme [9,10]. The mechanism of action of AChE has been elucidated in (Figure 1). The anionic sub site accommodates the positive quaternary amine of acetylcholine and other cationic substrates and inhibitors. The cationic substrates are not bound by interaction of 14 aromatic amino residues [11], which are highly conserved across different species [12]. Among these aromatic amino acids the substitution of tryptophan 84 with alanineresults in a 3000-fold decreased reactivity [13]. During neurotransmission, ACh is released from presynaptic neuron into synaptic cleft and binds to ACh receptors on the post-synaptic membrane, relaying the signal. AChE, also located on the post-synaptic membrane, terminates the signal transmission by hydrolyzingACh. The liberated choline is taken up again by the pre-synaptic neuron and ACh is synthesized by combining with acetyl-CoA through the action of choline acetyltransferase [14] (Figure 2).

Organophosphates (OPs), the esters of phosphoric acid, are a class of irreversible AChE inhibitors. The cleavage of OP by AChE leaves a phosphoryl group in the esteratic site, which is slow to be hydrolyzed and can bound covalently. Carbamates, esters of N-methyl carbamic acid, are reversible inhibitors of AChE that hydrolyze in hours and occupy the esteratic site for short periods of time (Figure 3). Presently, a combination of AChE reactivators such as atropine and diazepam are used for the treatment of OP poisoning. The drugs donepezil, galantamine, and rivastigmine used in alzheimer disease are inhibitors of AChE [9,15]. It has also been reported that some phytochemicals such as tetrahydrocannabinol, the active ingredient of cannabis, is a competitive inhibitor of AChE [16]. This article presents an updated account of the reports available concerning the alleviation of OP poisoning by some antidotes including atropine and oximes.

Interaction of cholinesterases with organophosphates

The physiological role of AChE in blood is not understood, but it was proposed that ChE may have roles in neurotransmission and involved in other nervous system functions and in neurodegenerative disorders [17]. In the presence of OPs, AChE becomes progressively inhibited and is not further capable of hydrolyzing ACh [18]. Consequently, ACh accumulates at cholinergic receptor sites and produces excessive stimulation of cholinergic receptors throughout the nervous systems. Both substrate and inhibitors react covalently with the esterase in essentially the same manner, because acetylation of the serine residue at AChE catalytic site is analogous to phosphorylation. Inhibited enzyme can be spontaneously reactivated at different rates depending on the inhibitor. The variations in the acute toxicity of OP are the result of their different chemical structures and rates of spontaneous reactivation and aging. The aging has the major clinical importance and an imperative problem in the treatment of pesticide poisoning because aged form of phosphorylated AChE is resistant to both spontaneous and oxime-induced reactivation. Hence, recovery of inactivated AChE function depends on relatively slow resynthesis of AChE during aging thereby exerting higher level of toxicity as compared to those at younger age.

Clinical presentation of OP poisoning

According to World Health Organization (WHO), in cases of intoxication the signs and symptoms of acute poisoning with OPs are predictable from their levels of AChE activity [19]. These clinical features include sweating, lacrimation, rhinorrhea, and abdominal cramps, salivation, respiratory difficulties, dyspnea, cough, wheezing, fasciculations, bradycardia, change in ECG, cyanosis, anorexia, nausea, vomiting, diarrhea, involuntary urination and defecation, accompanied by dizziness, tremulousness, confusion, ataxia, headache, tremors, constriction sensation in the chest, twitching of facial muscles and tongue, and fatigability finally into death. It has been reported that even after survival of the patient with OP poisoning, there would be mood swings, personality changes, aggressive events and psychotic episodes [20,21]. Diagnosis is relatively based on medical history, exposure circumstances, clinical presentation, and laboratory tests. Erythrocyte AChE is identical to the enzyme present in the target synapses and its levels are assumed to reflect the effects of OPs in target organs. Thus, erythrocyte AChE may be considered as a biomarker of neurotoxicity. Due to pharmacokinetic reasons, it is difficult to know exactly, how closely the AChE inhibition in erythrocytes reflects to that in the nervous system since access to blood is always easier than brain. Thus, erythrocytes AChE inhibition may reflect altogether a different message from that in brain [18].

Treatment of acute poisoning with Organophosphorus pesticides

Treatment of OP pesticide poisoning should begin with decontamination and care must be taken not to contaminate others.

Atropine

Atropine acts through blocking the effects of excess concentrations of acetylcholine at cholinergic synapses following OP inhibition of AChE. It has been reported that atropine may prevent development of convulsions and brain damage induced by certain OP [22]. The trial dose of atropine is 0.05 mg/kg intravenously, should be given slowly over 3 min, and then repeated every 5–10 min. In symptomatic children, intravenous dose of 0.015–0.05 mg/kg atropine should be administered at interval of every 15 min. Atropine may then be repeated at 15– 30 min intervals until the patient is atropinized (dilated pupils, dry skin, and skin flushing) which should be maintained during further treatment.

Diazepam

Benzodiazepines are central nervous system (CNS) depressants, anxiolytics (antipanic or antianxiety agent) and muscle relaxants. Marrs [23] in has reported that benzodiazepines, including diazepam, alter GABA binding in an allosteric fashion. The recommended dose of diazepam in cases of OP poisoning is 5–10mg intravenously in the absence of convulsions and 10–20mg intravenously in cases with convulsions [22].

Oximes

The antidotal potency of pyridiniumoximes is primarily attributed to their ability to reactivate phosphorylated cholinesterases. Reactivation proceeds through the formation of intermediate Michaelis-Menten complex leading to the formation of stable phosphoryl residue bound to the hydroxyl group of serine present at active site of AChE. The rate of reactivation depends on structure of phosphoryl moiety bound to the enzyme, source of the enzyme, rate of post inhibitory dealkylation and concentration of oxime [24,25]. Pyridiniumoximes are effective in the peripheral nervous system, but also have a penetration across the blood–brain barrier [26] and therefore enable passage of higher oxime concentrations into brain [27]. Pralidoxime is not sufficiently effective in the treatment of OP pesticide poisoning [28]. The inadequate initial treatment with oximes may not be sufficiently effective in OP poisoning because oximes are rapidly cleared from the body. Among the many classes of oximes investigated with clinical application can be divided in following groups: monopyridinium (PAM-2, pralidoxime), bispyridiniumoximes (TMB-4, trimedoxime), obidoxime (LuH-6, Toxogonin) and asoxime (HI-6).

Pralidoxime (PAM-2)

Sidell and Groff (1971) have shown that the pralidoxime administered to human at a dose of 10 mg/kg by intramuscular route, produced a plasma concentration of >4 mg/L within 5–10 min and maintained levels above this threshold for an hour [29]. The PAM-2 iodide was given in combination with atropine and diazepam, in the treatment of the victims of Tokyo sarin attack victims in 1995 [30]. However, PAM-2 should not be recommended against poisoning with warfare nerve agents due to its lack of efficacy [31].

Obidoxime

Obidoxime when administered to humans by intramuscular route, it produced a plasma concentration >4 mg/L, from 5 min after injection to 3 h [32]. Following high doses of obidoxime in severely OP poisoned patients; occasional hepatotoxic effects have been observed including increased serum transaminases and jaundice [33].

Asoxime (HI-6)

Asoxime is considered to be a very promising bispyridiniumoxime in treatment following exposure to most nerve agents. Studies showed that Asoxime dosed by intramuscular route reached plasma concentrations >4 mg/L in 4–6 min [34]. According to Jovanovi´c et al. [35] asoxime did not show any adverse effect on humans. The only disadvantage of asoxime compared to other available oximes is its lack of stability in aqueous solutions. Asoxime was considered to be an effective antidote in treatment of patients poisoned with OP insecticides [34].

Conclusion

The management of acute Organophosphate pesticide poisoning in humans includes general (decontamination and supportive measures) and specific treatment with atropine, oximes (pralidoxime, trimedoxime, obidoxime, and asoxime) and diazepam. Since the introduction of the antidotes in treating the patients poisoned with OPs, there is still no agreement on how these substances should be given for the best result following treatment. While the use of atropine and diazepam in humans have been widely accepted throughout the world., Pyridiniumoximes were successful in the treatment of most cases of OP poisoning, when given with atropine and diazepam. However, some reports indicate that treatment with pralidoxime was not sufficiently beneficial. These problems of effectiveness of oxime treatment may be solved in randomized clinical trial(s) comparing the WHO-recommended regimen with a placebo to assess the value of pralidoxime, and other oximes (obidoxime, trimedoxime, and Asoxime) as well, in acute poisoning with OPs.

Acknowledgement

Vivek Kumar Gupta is grateful to the University Grant Commission, New Delhi, for providing financial assistance in the form of a Research Fellowship.

For more Open Access Journals in

Juniper Publishers

please click on:

https://juniperpublishers.com

For more articles in

Anatomy Physiology & Biochemistry International Journal

please click

on:

https://juniperpublishers.com/apbij/index.php

For more

Open Access Journals

please click on:

https://juniperpublishers.com

To know more about Juniper Publishers please click on:

https://juniperpublishers.business.site/

[jorgemarquet]

Some ADHD Meds Tied to a Higher Psychosis Risk Than Others

Deborah Brauser

March 20, 2019

Amphetamines are associated with a higher psychosis risk than methylphenidate in young patients who take these agents to treat attention deficit hyperactivity disorder (ADHD), new research suggests.

Lauren V. Moran, MD

Stimulants are recommended as first-line treatment for ADHD. Although methylphenidate is the most frequently prescribed stimulant in many countries, amphetamines are the most commonly prescribed agents in the United States.

Assessing data on more than 220,000 adolescents and young adults starting on a stimulant for ADHD, investigators found that about 1 in 660 participants experienced new-onset psychosis in the following 4 to 5 months.

Among those patients, the risk for psychosis was almost twice as high with the use of amphetamines than with methylphenidate.

"For prescribers, I think the take-home point is that it's really important to screen for potential risk factors," such as a prior history of bipolar or other psychiatric disorder, a family history of psychiatric illness, or use of cannabis, lead author Lauren V. Moran, MD, assistant professor at Harvard Medical School in Boston and a psychiatrist at McLean Hospital, Belmont, Massachusetts, told Medscape Medical News.

"If patients have those risk factors, I would shy away from using the amphetamines. You don't want to have two things that could potentially further increase the risk for psychosis," she added.

The findings were published in the March 21 issue of the New England Journal of Medicine.

Little Comparative Research

Although the US Food and Drug Administration mandated labelling changes for stimulants in 2007 warning of the possibility of treatment-related psychotic or manic symptoms, current ADHD guidelines note that methylphenidate and amphetamines are the most effective treatments for the condition, "with no specification of preference for one over the other," the investigators write.

"Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied," they add.

The researchers note that both drugs cause the release of dopamine and inhibit the dopamine transporter.

"However, dopamine release is four times as high with amphetamine as with methylphenidate, whereas methylphenidate is a more potent inhibitor of dopamine transporters," they write. "The changes in neurotransmission observed in primary psychosis are more consistent with those induced by amphetamine."

Moran noted that there are many college students in the area around McLean Hospital and that in her anecdotal experience as a psychiatrist working in a unit that treats patients with psychotic disorders, she's "been seeing cases of young individuals coming in with psychosis" after stimulant use.

"Although the use of these medications has been rising rapidly, I was personally surprised that there's been no real comparison studies for psychosis risk — especially because there are subtle biological differences," she said.

Amphetamines the Preferred Choice

In the current analysis, the researchers examined patient records from two US insurance claims databases: Optum Clinformatics and IBM MarketScan. They initially assessed 337,919 patients between the ages of 13 and 25 years who were diagnosed with ADHD and who received a first prescription for a stimulant from January 2004 through September 2015.

The final study population comprised 221,846 patients — with half taking methylphenidate or dexmethylphenidate (the "methylphenidate group") and the other half taking amphetamine-dextroamphetamine, dextroamphetamine, or lisdexamfetaimine (the "amphetamine group"). Among the total group, there were 143,286 person-years of follow-up.

Interestingly, 3.8 times as many patients received an amphetamine prescription in 2015 than in 2005, but only 1.6 times as many patients received a methylphenidate prescription during the same time period.

"It's unclear to me what exactly is driving the increased preference of prescribers to start somebody on amphetamine as compared to the Ritalin-type drugs," Moran noted.

In addition, 72.5% of the participants treated by family medicine or internal medicine physicians received an amphetamine prescription, as did 51.6% and 63.7% of those treated by pediatricians and psychiatrists, respectively.

The primary outcome for the study was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis.

Diagnoses that qualified as psychosis included major depressive disorder or bipolar disorder with psychotic features, schizophrenia spectrum disorders, delusional disorder, hallucinations, and unspecified psychosis.

"We weren't really looking at transient symptoms of psychosis that go away after a couple of days. We were looking at more severe cases. A majority of the patients were hospitalized and discharged with a prescription for antipsychotics," Moran said.

To determine hazard ratios (HRs) for psychosis, propensity scores from patients who received methylphenidate were matched to those who received amphetamine in each database. The results were then pooled from both databases.

Psychiatrists More Cautious?

Results showed that 106 episodes of psychosis occurred in the full methylphenidate-receiving group (0.10%) vs 237 episodes that occurred in the full amphetamine-receiving group (0.21%).

The incidence rate of psychosis was 1.78 vs 2.83 episodes per 1000 person-years of drug exposure for each group, respectively. Median time from receipt of first stimulant to psychotic episode was 128 days.

The pooled HR for psychosis across both databases was 1.65 for the amphetamine group vs the methylphenidate group (95% confidence interval, 1.31 - 2.09).

Post hoc analyses showed that patients treated by family medicine/internal medicine physicians and pediatricians had a significantly higher risk for psychosis from use of amphetamine than with methylphenidate (HRs, 1.78 and 1.70, respectively) — but those treated by psychiatrists did not (HR, 1.38).

"However, the post hoc nature of the analyses and the inadequate power limit the interpretation of these findings," the investigators write.

"Patients referred to psychiatrists for ADHD may have cognitive deficits or behavioral features that are related to prodromal psychosis, and data on prodromal symptoms would not be captured in claims data. Psychosis may develop in these patients regardless of stimulant treatment," they add.

They also speculate that psychiatrists may be more cautious when prescribing amphetamines and may screen more for psychosis risk factors.

Moran noted that although the study wasn't a randomized controlled trial, "it reflects real-person practice. This is real-world evidence."

"Studies show that stimulants for ADHD might be more effective than non-stimulants, so it can be a little tricky. But definitely in someone who's had a psychotic reaction, or someone who has risk factors for psychosis, I'd avoid stimulants altogether," she said.

Debate Continues

"Despite meta-analyses that show the efficacy of stimulants in reducing ADHD symptoms, at least in the short term, the quality of evidence and the safety of these medications continue to be debated," Samuele Cortese, MD, PhD, Center for Innovation in Mental Health, University of Southampton, England, writes in an accompanying editorial.

He adds that there have been little data on the comparative risk for psychosis between methylphenidate and amphetamine.

The current results "are consistent" with a previous meta-analysis of randomized trials that suggested greater safety for methylphenidate, "at least at the group level," Cortese writes. But, he adds, the new findings "should not be considered definitive."

Study limitations cited include its observational nature, which cannot exclude confounding factors as well as a randomized trial would, and that it could not establish causality.

In addition, "whether psychosis is due to stimulant use, to inherent vulnerability to psychosis, or to the interaction of those factors remain unclear," Cortese writes.

"Despite uncertainties regarding causal mechanisms, the study by Moran and colleagues provides important data on the incidence of psychosis observed in routine practice among patients with ADHD," he adds. "These figures could inform decision making among patients, families, and physicians."

Cortese notes that although it isn't yet possible to identify which patients will have an episode of psychosis after being treated with a stimulant, strategies such as machine learning plus observational data may eventually "provide predictors at the individual patient level."

The study was funded by grants from the National Institute of Mental Health. Moran has disclosed no relevant financial relationships. Disclosures for the other study authors are fully listed in the original article.

N Engl J Med. 2019;380:1128-1138 and 1178-1180. Abstract, Editorial

[123emarket-blog]

Toronto man’s trial leaves many asking: Can excessive marijuana use lead to psychosis?

Toronto man’s trial leaves many asking: Can excessive marijuana use lead to psychosis?

Yes, smoking pot can trigger psychosis. But, no, smoking a few joints is not the equivalent of a “get out of jail free” card. That’s what we should retain from the case of Mark Phillips, who received a light sentence in an assault case after the court accepted the argument that the 37-year-old was suffering from “marijuana-induced psychosis.” The case has caused much consternation, for a couple of reasons. The assault itself was horrible: On Dec. 7, in St. Thomas, Ont., Mr. Phillips attacked a family of immigrants in a parking lot because they were speaking Spanish, breaking one man’s ribs with a baseball bat while yelling that he was a terrorist. The incident was filmed and posted on YouTube. He pleaded guilty to assault causing harm (after originally being charged with aggravated assault) and received a conditional discharge, meaning that after serving three years’ probation, doing 240 hours of community service and refraining from consuming all non-prescription drugs during the probation period, he will not have a criminal record. The sentence has miffed many. The case leaves the impression that a well-to-do white man (Mr. Phillips is a Toronto lawyer) has been treated with kid gloves by the courts. His defence – that his seemingly racist attack was caused by consumption of marijuana – has also been widely mocked. Let’s leave the arguments about race - and income - and status-based double-standards in the justice system to others and focus on the medical aspect of the case – namely: Can cannabis cause psychosis? That question is hotly debated in scientific circles and the answer seems to be a mitigated yes. First, we need to understand what psychosis is - a mental disorder in which thought and emotions are so impaired that contact is lost with external reality. (It is not the same as hallucinations.) Psychosis is quite rare – fewer than three in 100 people will experience a psychotic episode in their lifetime. People who smoke or otherwise consume cannabis, especially in significant quantities, have a higher incidence. But correlation is not the same as causation. Some people have vulnerability, a genetic predisposition to psychosis, and cannabis can be a trigger, as can other things like trauma or amphetamines. Severe mental illness like schizophrenia tends to arise in late teens and early adulthood, the same time young people tend to experiment with drugs, so the psychosis can be coincidental. Finally, many people with severe mental illnesses that feature psychotic episodes self-medicate, with cigarettes, alcohol and cannabis. In other words, it’s a classic chicken-and-egg scenario: It’s not clear which comes first, mental illness or cannabis use. There are also incidents recorded where consuming significant amounts of cannabis seems to be an actual trigger for psychosis – and that’s what the court heard from an expert witness in the case of Mr. Phillips. The evening of the attack he smoked at least three or four joints. He did so routinely, and also routinely felt he was being threatened by terrorists. Mr. Phillips told his therapist that he has been purchasing cannabis at dispensaries, six to eight grams at a time, for a significant time period. This was not casual use. Dr. Peter Collins, a forensic psychiatrist at the Centre for Addiction and Mental Health in Toronto, also said Mr. Phillips’s symptoms of paranoia and his feelings of persecution dissipated when he was not smoking cannabis. What is fascinating, and little discussed about this case, is that Mr. Phillips did not claim he was “not criminally responsible” due to mental illness. That would be a much harder case to make. He actually pleaded guilty, but said his cannabis-induced psychosis should be a mitigating factor in sentencing – a position that was accepted by both the Crown prosecutor and the judge. One can debate whether or not the court was right to grant him some slack. But there is little evidence that this case will set much of a precedent. The argument made in the case was not that someone impaired by cannabis cannot commit a crime but rather that, in rare instances, cannabis use can cause temporary mental illness. That’s a tough case to make and it’s going to be even tougher to make after the scrutiny this ruling has rightfully inspired. Read the full article