Pharma – David Bradley

What are nitazenes? Benzimidazole opioids

Benzimidazole opioids, also commonly known as nitazenes, were first synthesised by CIBA Pharmaceuticals in the 1950s as putative alternatives to morphine and heroin for use as strong painkillers. They have never made it into use in clinical medicine because the risk of addiction, respiratory depression, and death in use is too high.

Etonitazene has hundreds of times the potency of morphine

The compounds are classified as opioid New Psychoactive Substances (opioid NPS). Their mode of action is to bind to the brain’s mu-opioid receptors, but their unique structure means that some examples are several hundred times more potent than morphine and stronger even than fentanyl.

The changing heroin market led to the emergence of nitazenes as drugs of abuse in the early 2020s if not earlier. They pose a major new problem for public health and law enforcement.

Nitazenes were first in the UK news in 2021, when an 18-year-old patient was treated for overdose. Since then, there has been a rise in nitazene abuse with more than fifty overdose deaths and perhaps many more that remain inconclusive. Several nitazenes are, as of this week, defined as Class A drugs in the UK.

On a point of chemical semantics, opiates are chemicals derived from opium or poppy straw. They are alkaloid compounds naturally found in the opium poppy plant, Papaver somniferum. The archetypal opiate is the compound morphine. The analgesic pro-drug codeine is converted in the body to morphine. Heroin (diamorphine) is extracted from the dried latex of the poppy and has a very similar chemical structure to morphine.

The term opioid is used to designate any substance, natural or synthetic, that binds to the opioid receptors in the brain. So, this includes morphine and heroin, but also compounds that are not chemically related to the opiates such as fentanyl, which is a piperidine, and the nitazenes, which are benzimidazoles. There are many different benzimidazoles used safely in pharmaceuticals for treating high blood pressure, fungal infections, parasitic worms etc.

Anti-covid, antiviral ensitrelvir

TL:DR – An antiviral drug called ensitrelvir could cut the time a person tests positive when they have COVID-19 by about a day. There is a controversial suggestion that it might also reduce the risk of developing long-covid.

An antiviral drug developed by Shionogi in partnership with Hokkaido University is an orally active 3C-like protease inhibitor, which can shorten the time between first testing positive after infection with SARS-CoV-2 and getting a negative test. Early signs are that it may well reduce the risk of developing long-covid, although that data is yet to be peer reviewed. There are some scientists sceptical of the claim having heared the results presented at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington, USA, in February. They suggest that more work in clinical trials is needed before the claim can be accepted. Mariana Lenharo has all the details in Nature.

Long-covid is also known as long-haul COVID, post-COVID-19 syndrome, post-COVID-19 condition, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS). The term describes the long-term symptoms and effect on various body systems and organs following infection with SARS-CoV-2.

Currently, there are two orally active antivirals for treating COVID-19, Paxlovid (nirmatrelvir/ritonavir) and molnupiravir. The antiviral ensitrelvir has the brand name Xocova.

The controversy surrounding whether or not ensitrelvir can reduce the risk of a person developing long-covid is about whether or not the trials and the definitions offered by Shionogi on this point are valid. There had previously been a more general suggestion that shortening the time that a person tests positive for COVID-19 could be beneficial. That said, there is evidence that even those who only have mild symptoms of COVID-19 can still develop long-covid. It could be that long-covid is a side effect of the body’s immune response to infection rather than being due to residual virus. There is much we are yet to learn about this virus.

Meet GINA, Global INitiative for Asthma

TL:DR – Thanks to GINA I have not needed to use salbutamol to treat my asthma for three years at the time of writing.

It’s three years since my asthma nurse introduced me to GINA, the Global INitiative for Asthma. It was a phone consultation because the then new virus SARS-CoV-2, which causes what became known as COVID-19, was beginning to spread. At the time, I was very worried that it would be a killer for me given my asthma. Eventually, medical science learned that people with asthma were not necessarily at any greater risk of morbidity and mortality.

Anyway, it was nice to meet GINA. GINA contradicts some of what general practitioners (GPs) in the UK have been advising asthma patients for years, but supports what the medical evidence suggests one should do in terms of medication. The main thing is GINA told me to stop using Salbutamol (the reliever spray) and to use my Symbicort (combined preventer with reliever spray) instead. Salbutamol is an old, out-of-date drug with some unpleasant side effects in long-term use, partly because it can affect the heart but mainly because inappropriate use in the absence of proper control of the condition with a preventer can lead to scarring in the lungs.

Modern relievers are more targeted to the lungs rather than other organs. Moreover, using the preventer at a higher dose, which is what my nurse recommended, means you reduce inflammation and mucus production, which are the main issues with asthma in parallel with episodic bronchoconstriction.

For three years, I have been taking twice as much preventer each day as I was before, and only very occasionally need to take extra to get a dose of reliever. I have not used Salbutamol at all in those three years and don’t expect to have to ever again. I no longer carry Salbutamol with me.

A GP friend was concerned when I told him about GINA, he reasoned, quite sensibly that taking this approach would be increasing one’s exposure to the preventer drugs, which are corticosteroids. This is true. But asthma is mostly about inflammation and these drugs reduce inflammation and so should reduce asthma symptoms. They do. He discussed the issue with colleagues and is now persuaded that GINA is a more sensible approach to asthma control than the current NICE recommendations in the UK. Hopefully, someone will introduce NICE to GINA soon.

Supplementing physical and mental health

TL:DR – Anecdote is not evidence, but I feel like I gained some benefit from taking a multivitamin supplement, it probably compensated for poor absorption of iron and perhaps other vitamins caused by one of my prescription medicines.

I’ve always been wary of taking vitamins and other supplements. There are good reasons not to do so, if you have a reasonably balanced diet. Excesses of some vitamins and minerals can lead to problems like kidney and liver damage, kidney stones, and some can interfere with the absorption and activity of prescription medicines.

However.

I have been feeling rather tired in recent months, becoming unaccustomedly exhausted after even light activity. I’m talking after a short walk, but sometimes even just after a shower. Was it long-COVID, was it my medication, was it just me getting older?

Mrs Sciencebase had an iron and vitamin supplement for an unrelated reason and suggested I try it, see if it would help.

Well, I took the recommended dose for a few days, not expecting to experience much improvement. Amazingly though, I felt a remarkable change in what people commonly refer to as “energy levels”. Activities that had started to become a tiring chore became a lot easier, I hopped on my bike and did a decent half an hour’s cycling without breaking a sweat, a couple of days after that I did an hour, at speed, and aside from being thirsty when I got back to base, I was fine.

I know anecdote is not evidence, but honestly, it seems like too much of a coincidence that I felt like I had recovered from apparent chronic exhaustion within three days or so of taking the supplement. Moreover, when I look at the side effects of one of my medications, it does suggest that tiredness and various other side effects are associated with reduced absorption of micronutrients (vitamins and minerals). So, I’m sticking with the supplement for a while longer.

Intriguingly, the effects do not seem to have been wholly physical though. Most people have had a tough few years, but there has been significant family loss and stress here that happened in the middle of covid, is ongoing, and I have not been what you might call the happiest bunny in the warren, for a long tim, I must confess. Stuff that I usually really enjoy has not, on too many occasions, brought me much joy in recent months. I shrugged it off as being the grief and worry…but…a few days ago, I felt like the proverbial cloud had lifted, and even though it was a drizzly day, the sun seemed to be shining again.

Could this too have been a supplement fix? Well, there are many, many biochemical pathways that are linked to mental health, disturbance in some of those are known to be connected to depression. These various pathways need various micronutrients to work properly. Might I have been deficient in an essential biochemical component? Have I now replenished my supplies and rebooted those pathwats?

Perhaps the brain, when faced with deficiency, goes into some kind of lockdown to make you mope, reduce motivation, and so activity? And, when that lockdown is prolonged and deep, could it also begin to impinge on other pathways to the detriment of mental health. If so, I wonder if this is exacerbated in the wake of a double-dose of grief accompanied by a lot of not unwarranted stresses and anxieties.

I don’t know. Like I say, anecdote is not evidence. I’d rather not take the supplements for a prolonged period of time, so I will be having a chat with my doc at my annual review about my current medication. I will tell them that what I do know is that I’ve been taking a daily dose of micronutrients and feel physically much fitter than I have for a long time and mentally far brighter.

As a footnote, I shared this post on my Mastodon and a couple of people suggested that my experience may be due to my “taking control” or simply a placebo effect. Well, that is a possibility, of course. However, I’ve had symptoms for a long time that coincide with several mentioned on the documentation accompanying one of my medications and I feel that reversion to the mean/norm (basically, the placebo effect) was so sudden and coincided with taking the supplement that there must have been a physical effect of doing so rather than my spontaneously recovering…but, again, anecdote is not evidence, either way. One cannot do double-blind, placebo-controlled studies on oneself.

Vaccination NOW

TL:DR – At the time of writing, vaccination of COVID-19 was getting underway. It is still highly recommended despite the disinformation, fake news, and conspiracy theories.

In a few month’s time, the first 10 million people will have been vaccinated against covid. Within two months, 4000 of those people will have a heart attack, 4000 will have a stroke, 10000 will be diagnosed with cancer, 14000 will die.

How many of those illnesses and deaths will be due to the vaccination? None of them.

But, the antivaxxers will start to claim some of those 4000 strokes, those 10000 cancers, those 14000 deaths as being caused by the vaccine. They will be wrong to do so. Why, because if we were to start counting 10 million people from today, none of them yet vaccinated against covid, within two months, 4000 of those people will have a heart attack, 4000 will have a stroke, 10000 will be diagnosed with cancer, 14000 will die.

If you know 100 people of all different ages and demographics, then one of them will have a heart attack within the next four years, one of them will have a stroke in that time, a couple of them will be diagnosed with cancer, and in those same four years, 2-3 will actually die. That’s the statistics. If you’re one of somebody else’s 100 friends, then you could be in any of those groups. This is the normal of life, disease, and death.

In the new-normal of the covid world, we need as many people as possible to be vaccinated to quash the spread of this new virus, otherwise there will be much bigger numbers to record in all of the above.

Drug discovery scientist Derek Lowe has much more to say on this topic having built on a twitter thread from Bob Wachter (Chair, University of California San Francisco Department of Medicine).

Of course, once we’re vaccinating millions of people, there will be some side effects and there will be some effects that arise that might be caused by the vaccine or just other random effects of the human condition. The fact is though, that the morbidity and mortality rates for covid will far outstrip any side effects of adverse reactions seen in the people who get the vaccine, this much is true from the trials of thousands of people who have been tested with the vaccine already.

The antivax movement will jump on every disease, every death gleefully proclaiming that the vaccine is to blame. But, 14000 in every ten million people would die in any random two month period before we’d even heard of covid. Now, that we have covid with us that is an extra cause of death to add to our terminal list. Vaccination will minimise those extra deaths, so that hopefully none of us will lose too many of our 100 friends to this dreadful disease.

Adverse effects of hydroxychloroquine

UPDATE: If you have been prescribed this drug for another condition, do not stop taking it without consulting your GP. Your GP will have prescribed it for a good reason and will know your medical history and undertaken a risk-benefit assessment before signing your prescription. The majority of the side-effects are rare and it is generally safe to use for the approved conditions if heart problems and other underlying possible complications and contraindications have been ruled out for you.

In case you were ever stupid enough to follow Trump’s lead you would have already injected ultraviolets in your eyeballs by now to save you from Covid and maybe bathed in Domestos or sulfuric acid or both! Anyway, his latest bullshine claim is that he’s been taking the antimalarial drug hydroxychloroquine to keep Covid at bay.

Well, for starters there is no evidence that this drug acts as a prophylactic against infection with SARS CoV-2 or indeed any pathogen other than the causative agent of otherwise drug-resistant malaria. It’s primary use is in treating lupus. There was some testing done weeks ago to see whether it might work against SARS-CoV-2, it almost certainly doesn’t, there will be actual antivirals to try and some being developed as we speak.

Either way, did anyone actually do a benefit-risk balance assessment for him or has he self-medicated on a whim? I strongly suspect that he is not taking it at all and that there is some hidden agenda. As with everything else he says bullshit or otherwise a political or financial incentive is often at the front of his frothing, festering mind.

The US Food and Drug Administration warns against taking this drug outside the clinical environment because it can cause serious and potentially lethal heart problems”. If you were thinking of taking inspiration from The Trunt listen to the FDA or maybe have a look at the huge list of post-approval adverse reactions and side-effects already reported for hydroxychloroquine:

Bone marrow failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia, hemolysis in people with G-6-PD enzyme deficiency, Cardiomyopathy and fatal cardiac failure, ventricular arrhythmia, Vertigo, tinnitus, nystagmus, nerve deafness, deafness, eye irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance), visual field defects, and visual disturbances, macular degeneration, corneal edema and opacity, nausea, vomiting, diarrhea, and abdominal pain, fatigue, liver failure, urticaria, angioedema, asthma, poor appetite, hypoglycemia, porphyria, weight loss, sensorimotor disorder, skeletal muscle myopathy or neuromyopathy leading to weakness and muscle wasting, failing tendon reflexes and abnormal nerve conduction, headache, dizziness, seizure, ataxia and dystonia, dyskinesia, and tremor, emotional problems, nervousness, irritability, nightmares, psychosis, suicidal thoughts, rash, pruritus, pigmentation disorders in skin and mucous membranes, alopecia, skin eruptions, toxic epidermal necrolysis, photosensitivity, psoriasis…

The complete, detailed list of ADRs and side-effects can be found here.

What is Esketamine?

You may have seen that an antidepressant called “Esketamine” has been approved for use in the UK. Sounds a bit like ketamine you’re thinking, and you’d be right. It is a purified form of the more well-known drug, commonly thought of as a horse tranquiliser and often used as a drug of abuse.

Many drug molecules come in two forms, what you might refer to as a left-handed and a right-handed form. When they are manufactured, both the left (known as the S) and the right (labelled R) form are produced, usually in equal quantities. Often one form, R or S is more active than the other, as is the case with the painkiller ibuprofen.

Sometimes, one form is active and the other form causes side effects. This is the case with thalidomide, although the forms are interconverted in the body so it is impossible to make a safe form of that particular drug for women who are or might get pregnant.

Standard manufacture of ketamine produces the R and the S form, (R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. The R form, interacts with additional receptors in the body that are not the chosen target of the drug and so lead to side effects. Hence, the need to produce ketamine as the S form only for use in treating depression. The drug S-ketamine, thus becomes esketamine. The S form is twice as potent as the mixture of R and S. The R form is nominally arketamine, clever naming.

Esketamine is marketed as Ketanest and Spravato, commonly used as a general anesthetic (intravenous) and now for severe, treatment-resistant depression (nasal spray). The drug acts by blocking the NMDA (N-methyl-D-aspartate) receptor in the nervous system and also acts as dopamine reuptake inhibitor. Dopamine release is associated with pleasure and feelings of reward, these feelings can, theory goes, be made to last longer if the dopamine remains active and is not “reuptaken” back into nerve cells too quickly.

Ketamine can be addictive and so can its S enantiomer, esketamine, which as mentioned has now been approved in the UK. Some physicians are concerned about its use. Addictive nature aside, there is the issue that esketamine increases glucose metabolism in the frontal cortex of the brain and this may be responsible for the more psychologically dissociative and hallucinogenic effects of esketamine. Arketamine decreases glucose metabolism in the brain and is thus reportedly more relaxing.

On balance, the ratio of benefits to risk is considered high enough that it can be safely used for some patients with severe and very debilitating forms of depression.

Footnote

The one thing I’ve not yet ascertained is whether or not the manufacture of esketamine begins with the 50:50 racemic mixture of the R and S forms and involves their separation prior to formulation of esketamine or whether the manufacturer has an enantioselective synthetic route that gives them a bigger proportion of the S form and less waste when they remove the R form prior to formulation. Luddchem pointed out a cyclodextrin paper published by Wiley here.

Vitamin D supplements

We need vitamin D, although exactly what you mean by vitamin D is open to debate, there are several different chemicals that come under the umbrella of that term and you won’t always get the most appropriate from a supplement. Indeed, a given product might not even tell you which form you’ve bought over the counter. This beggars the question, what is it exactly that the SACN report commissioned by the UK government is recommending we take? The report suggests that many of us don’t go outside enough to get adequate exposure to sunlight for vitamin D production in our skin (sunscreen blocks the UV necessary to make the stuff, ironically enough). So, we should all be taking vitamin D in the autumn and winter and some of us all year round…

There’s been a massive backlash against taking vitamins, antioxidants and other supplements because it seems that they can sometimes do more harm than good unless you have a specific condition or deficiency. Indeed, there are no good clinical trials that show any benefits to any otherwise healthy person with a half-decent diet of taking any food supplements at all. It’s all marketing hype all that stuff about extracts and essential oils. Pure quackery. So, is it any surprise that this new “research” by a government-commissioned body is now suggesting that we take vitamin D supplements?

Would we be hearing about it in the news this week if the agency’s conclusion had been to not recommend taking extra vitamin D? Doesn’t it just smack a little of industry lobbying to get such studies carried out in the first place, because they’re almost always bound to err on the side of caution and make a positive suggestion with respect to the subject rather than a negative one and pretty much disregard the risks of overdosing on fat-soluble vitamins, which is a real issue?

There is, of course, a case for vitamin D and other supplements and nobody wants the widespread return of rickets, which is caused by a deficiency, but it does feel like more than a coincidence. Other similar suggestions from health bodies will follow, just you watch…

What is fentanyl?

UPDATE: 2018-08-06 Fentanyl is in the news again with new stats and warnings about deaths. Of course, heroin and morphine still account for most illicit drug poisonings (overdoses).

Fentanyl, N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide, is a synthetic opioid type analgesic invented in 1959 but introduced only in the 1990s for palliative care in terminally ill patients. It is 80 to 100 times more active than morphine and about 40 to 50 times stronger than heroin (diamorphine). It also goes by the name of fentanil (sic), Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl, Abstral, and Lazanda1. It works quickly and its effects last only a short time as it trips the mu-opioid receptors in the brain.

It is widely used in medicine (often in skin patches) but, is also a drug of abuse and has been since the 1970s. Unfortunately, its strength means overdosing is a serious risk leading to respiratory collapse rather than liver failure. There have been several prominent cases in the last few months and pundits are talking of a fentanyl epidemic. Perhaps the most prominent recent case is the accidental death of pop star Prince (Prince Rogers Nelson) in April 2016. The Midwest Medical Examiner’s Office announced on 2nd June its findings regarding his death and concluded an accidental death from fentanyl toxicity. You can read the Office’s PDF press release here. Deaths from fentanyl overdose in the drug community are, in some US states, such as New Hampshire, far outstripping heroin overdoses, according to the New York Times. It is, worryingly, used increasingly by drug dealers to cut heroin.

Fentanyl was used by the Russian security forces in a spray to incapacitate people in the Moscow theatre hostage crisis in October 2002. Some 130 of the 850 hostages died from respiratory problems and choking having not received adequate medical attention once the siege was ended, essentially they were not put into the recovery position. BBC report.

As with most drugs of abuse, they are rapidly and widely adopted by popular culture. Fentanyl has many street names including Apache, China Girl, China White, Dance Fever, Goodfella, Jackpot, Murder 8, and TNT.

Updates from March that were shown to be irrelevant

UPDATE: 2018-03-08 As unlikely as it ever sounded, fentanyl was not the ‘agent’ used to attack Skripal and his daughter. Official line is a nerve agent, although they’re not saying which, probably VX. [[Turned out to be a generic Novichok agent that is yet to be identified publicly as of 2018-08-07]]

2018-03-06 Fentanyl is in the news again today with suspicions that it was used to poison Russian former Colonel Sergei Skripal (66) and his 33-year old daughter who was visiting from Russia. Both were seen sitting apparently catatonic on a park bench in the English town of Salisbury, Wiltshire, and eventually taken to the local hospital emergency department. Reports suggest that the pair had eaten at a Zizzi restaurant earlier in the evening. One witness claimed to have seen the man vomiting. Paramedics attended and a police “specialist chemical response unit” had removed an “unknown substance” which had been wrapped in several protective layers. Of course, you don’t lock down a whole A&E department because someone has OD’ed on fentanyl…I will update as and when.

Zinc, the only supplement

SECOND UPDATE: From Sciencebased Medicine [no relation]: “While zinc has the ability to inhibit rhinovirus replication in the test tube, clinical trials for the treatment of colds have been disappointing. While there was a very modest improvement in symptom score in one study of adults, the benefit was seen only when zinc was taken in large doses 5-6 times per day. At these doses, GI side effects were significant and patients complained of a bad taste in their mouth. Needless to say, 5-6 times per day dosing with these side effects would preclude this as a viable option in children. Additionally, a well-designed, randomized, double-masked, placebo-controlled study demonstrated no effectiveness of zinc on cold symptoms in children and adolescents.”

UPDATE: I just took a look at the packet of Zn tabs I have, 15mg per tab. The Cochrane Review says effective dose seen at 75mg. So…who’ve I been kidding? Anecdote is not evidence.

Zinc is the only supplement I take if I feel a cold coming on. Vitamin C, echinacea, cod liver oil etc have no proven effect. But, recent Cochrane analysis vindicates earlier research on which I based my choice.

Zinc – The promise: Laboratory studies have found it can inhibit replication of the rhinovirus, the most frequent cause of cold symptoms.

The research: A Cochrane review of 18 good quality studies last month found that zinc lozenges or syrup significantly reduced the average duration of the common cold in healthy people when taken within 24 hours of the onset of symptoms.

Dr Mullen says: ‘Zinc influences the immune system in a number of ways: it is involved in immune cell recruitment and function, systemic inflammation, is an antioxidant, and may have antiviral properties with respect to the common cold.’

The verdict: A proven treatment for colds, although side effects include a bad taste and nausea. The review advises taking zinc lozenges of 75mg or more until there is more research.

There is one caveat, I remember my old GP telling me he was involved in a Cambridge U study on cadmium content of zinc supplements. Cadmium is toxic, don’t know what the conclusion of his research was, never been able to find it on PubMed. But, either way, it’s a risk-benefit equation you have to balance yourself. Just don’t waste your money on the remedies that are really nothing more than expensive placebos (homeopathy and Reiki therapy for instance), they will do nothing to tackle a viral or any other infection.

Do supplements really help us keep healthy in the winter? – Telegraph.

Work in 2001 suggested that cadmium can indeed be present in zinc supplements – http://www.ncbi.nlm.nih.gov/pubmed/11474903, other work highlighted the fact that zinc is protective acute exposure to cadmiu – http://www.ncbi.nlm.nih.gov/pubmed/23726800