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Drugs and devices

Clinical Articles

The Vit D Story Now a Fairytale

It wasn’t that long ago that vitamin D appeared to be the panacea for everything from preventing MS to reducing the risk of diabetes.But the one area where we thought the benefit of this vitamin was not up for debate was bone health.It has been proven - lack of vitamin D causes rickets. It has been proven that vitamin D is important in bone metabolism and turnover. And it has been proven the people with low bone density are more likely to experience fractures. Therefore add vitamin D and improve bones, right? Wrong!The latest meta-analysis of more than 80 randomised controlled trials shows that vitamin D supplementation does not prevent fractures or falls, and does not have any consistently clinically relevant effects on bone mineral density. This comes as a bit of a surprise, to say the least.According to the systematic review, vitamin D had no effect on total fractures, hip fractures, or falls among the 53,000 participants in the pooled analysis.And it didn’t matter if higher or lower doses of vitamin D were used, the New Zealand researchers reported in The Lancet.In looking for a reason for the lack of an effect from supplementation, previous explanations such as baseline 25OHD of trial participants being too high, or the supplement dose being too low, or the trial being done in the wrong population just don’t hold water. The sheer number and variety of trials included in this meta-analysis has meant all of these possible confounders have been accounted for.“The trials we included have a broad range of study designs and populations, but there are consistently neutral results for all endpoints, including the surrogate endpoint of bone mineral density,” they said.Consequently, the researchers said future trials were unlikely to alter these conclusions.“There is little justification to use Vitamin D supplements to maintain or improve musculoskeletal health,” they stated.And while they acknowledge the clear exception to this is in the case of the prevention or treatment of rickets and osteomalacia, in general clinical guidelines should not be recommending vitamin D supplementation for bone health.The conclusion appears quite emphatic and definitive, and it is supported in an accompanying commentary by a leading US endocrinologist.“The authors should be complimented on an important updated analysis on musculoskeletal health,” said Dr Chris Gallagher from Creighton University Medical Centre, Omaha in the US.But he suggests many Vitamin D supporters will still be flying the flag for supplementation, pointing to the multiple potential non-bony benefits.“Within three years, we might have that answer because there are approximately 100,000 participants currently enrolled in randomised, placebo-controlled trials of vitamin D supplementation,” he said.“I look forward to those studies giving us the last word on vitamin D.”

References

Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018 Oct 4. Available from: http://dx.doi.org/10.1016/S2213-8587(18)30265-1 [epub ahead of print]Gallagher JC. Vitamin D and bone density, fractures, and falls: the end of the story? Lancet Diabetes Endocrinol. 2018 Oct 4. Available from: http://dx.doi.org/10.1016/S2213-8587(18)30269-9 [epub ahead of print]

Expert/s: Dr Linda Calabresi

Drugs and devices

Clinical Articles

Phenibut – the Russian anti-anxiety drug linked to Gold Coast teens’ overdoses

Phenibut was initially developed in the 1960s in Russia as an anti-anxiety (anxiolytic) drug with cognitive enhancing properties. It has since attracted a strong following of users in the “smart drug” market, with claims of boosting memory recall and exam performance.Originally given to Soviet cosmonauts to combat anxiety and insomnia, the powdered drug is suspected to have played a role in the recent overdose of seven teenagers at a Queensland private school.

How it works

Phenibut – also known as pbut, noofen, party powder (or its scientific name β-phenyl-γ-aminobutyric acid and brand name Bifren) – is a psychotropic drug, which means it affects the user’s mental state.The drug is similar in structure to a type of neurotransmitter known as neurotransmitter γ-aminobutyric acid (GABA), which plays a role in reducing excitability and anxiety, as well as enhancing euphoria and cognitive function. Phenibut binds to a specific subtype of the GABA receptor, activating a similar reaction as GABA.Animal studies have shown that phenibut is able to penetrate the blood brain barrier. The blood-brain barrier is is an important mechanism that stops harmful toxins and bugs travelling through the blood stream and entering the brain.

Read more: Explainer: what is the blood-brain barrier and how can we overcome it?

Once phenibut reaches the brain the result is reduced anxiety and social inhibition. Because it depresses the central nervous system (like GABA), it is also used as a mood elevator and tranquiliser.Phenibut is structurally similar to the widely prescribed drug baclofen (Lioresal), which is available in Australia. Baclofen is prescribed as a muscle relaxant for patients with conditions such as multiple sclerosis.

What is it used for?

Phenibut can be used to treat anxiety, post-traumatic stress disorder, alcohol withdrawal syndrome and vestibular (balance) disorders such as vertigo. It is also used recreationally in many countries including the United States, United Kingdom and Australia to reduce social anxiety and induce feelings of euphoria.Animal studies also show it has potential to improve brain function after a stroke.Phenibut is not licenced for use in the European Union, Australia or the United States due to safety concerns. In Australia specifically, the drug regulator, the Therapeutic Goods Administration (TGA) has rejected 11 public submissions for registration and states that phenibut “represents a significant risk of harm, including overdose”.Although phenibut is commercially available in few countries around the world, aside from Russia, a recent study showed that 48 unrelated internet suppliers sold phenibut from the United Kingdom, United States, China, Australia and Canada. In Russia and the Ukraine, it is commercially available as БИФРЕН® (Bifren) and daily doses range from 500 to 2000 mg.Phenibut was available as a powder in amounts ranging from 5 g to 1,000 kg and as capsules containing 200–500 mg in packs of between six and 360.

How was was it developed?

Phenibut was first synthesised in Russia in the 1960s by Vsevolod Vasilievich Perekalin and his associates at the Department of Organic Chemistry of the Herzen Pedagogical Institute in St Petersburg, Russia. In initial publications, phenibut was known as phenigamma.The drug used to be included in medical kits for cosmonauts on Russian space flights due to the reports of enhanced cognition and high tranquilising properties.

Side effects

Side effects of phenibut are generally linked to its central nervous system depressant effects, such as sedation and problems with breathing.There is currently limited information about phenibut. But because it has similar pharmacological properties to baclofen it’s likely to have similar side effects.

Read more: Explainer: how do drugs work?

These include gastrointesinal symptoms (nausea, vomiting, diarrhoea), central nervous system symptoms (insomnia, confusion, euphoria, depression, hallucinations), and visual disturbances and musculoskeletal symptoms (such as tremors).Users of phenibut can also develop tolerance within days, needing more of the drug to feel the same effects. This can increase the risk of adverse effects. Users may develop withdrawal effects, such as severe rebound anxiety and insomnia, when they stop taking the drug.Despite phenibut not being registered or legally available in Australia, the TGA has received three reports of problems related to phenibut use in the past five years. These cases range from isolated symptoms of headaches, to a cluster of symptoms such as visual impairment, muscle spasms, palpitations and nausea/vomiting.Signs of overdose include: shallow irregular breathing; drowsiness and lethargy; increased sweating; decreasing blood pressure; nausea and vomiting; and lowering body temperature.The reported adverse events of phenibut are just scratching surface of a largely unregulated online drug market with no standards of quality assurance. So for those students seeking the competitive edge, it looks like those extra marks are not worth it after all.Janet Cheung, Lecturer in Pharmacology, University of Sydney and Jonathan Penm, Lecturer (Pharmacy), University of SydneyThis article was originally published on The Conversation. Read the original article.

Expert/s: Dr Janet Cheung, Dr Jonathan Penm

Drugs and devices

Clinical Articles

Green light for ginkgo

Ischaemic stroke patients are less likely to deteriorate mentally if they take ginkgo biloba extract in addition to low-dose aspirin in the acute phase, a new study suggests.“Cognitive decline after stroke can result in vascular cognitive impairment and Alzheimer’s disease,” the study authors wrote.Importantly then, this randomised controlled trial showed stroke patients who took ginkgo as well as aspirin had better memory function, executive functions, neurological function and daily life in the six months after experiencing their stroke than those patients who took aspirin alone.The Chinese study also showed that taking ginkgo was not associated with an increased incidence of adverse events.The results of the study, published in the journal, Stroke and Vascular Neurology support the long-held hypothesis that ginkgo protects against neuronal death caused by ischaemia, which had been demonstrated in animal stroke models.It has been suggested that the possible mechanism of ginkgo’s effectiveness may include anti-apoptosis and increasing cerebral blood flow. In the study, researchers randomised over 340 patients, from five hospitals who had had an ischaemic stroke in the previous seven days to receive either 450mg of ginkgo biloba extract with 100mg aspirin daily or only the 100mg of aspirin daily.Both groups were treated for six months and were various intervals over that period. From the very early assessments (at 12 days) and through until 180 days, the difference in the assessments of cognitive and executive function was statistically significant. Similarly neurological and global function was significantly better in the group that took ginkgo.“These data suggest that [ginkgo biloba extract] is effective and could be recommended in the treatment of acute ischaemic stroke,” the study authors concluded.Ref: Li S, et al. Stroke and Vascular Neurology 2017; 0:000104. doi:10.1136 /svn-2017-000104

Expert/s: Dr Linda Calabresi

Drugs and devices

Clinical Articles

Assassination by pacemaker: Australia needs to do more to regulate internet-connected medical devices

In the future, people are going to be just a little bit cyborg. We’ve accepted hearing aids, nicotine patches and spectacles, but implanted medical devices that are internet-connected present new safety challenges. Are Australian regulators keeping up?A global recall of pacemakers has sparked new fears and splashy headlines about hacked medical devices. But the next 20 years of medicine will normalise the use of intelligent implants to control pain, provide data for diagnostic purposes and supplement ailing organs, which means we need proper security as well as access in case of emergency.
Read More: Three reasons why pacemakers are vulnerable to hacking
Pharmaceuticals and medical devices in Australia are regulated by the Therapeutic Goods Administration (TGA), an arm of the national Health Department.Can we rely on Australia’s medical devices regime? Recurrent criticisms by parliamentary committees and government inquiries suggest the regulator may be struggling.

The job of the TGA

The TGA regulates medical devices such as stents, pacemakers, joint implants, breast implants, and the controversial vaginal mesh that has featured recently in the media (and a Senate inquiry) over claims it seriously injured patients.The role of the TGA is vital, because defective devices can result in injury or death. They have a major cost for the public health system and affect patient quality of life. They often result in litigation, sometimes with billion-dollar settlements.In undertaking its mission, the TGA looks to information from manufacturers and distributors, from overseas regulators and its own staff.Like counterparts such as the US Food and Drug Administration, TGA staff are under pressure to get products into the marketplace and reduce “red tape”.

The TGA and cybersecurity

Wireless medical devices need greater security than, say, an internet-connected fridge. It is axiomatic that they must work.We need to ensure that information provided by the devices is safeguarded and that control of the devices – implantable or otherwise – is not compromised.To do that, we can use existing tools such as robust passwords, encryption and systems design. It also requires product vendors and practitioners to avoid negligence. Regulators must proactively foster and enforce standards.Put simply, bodies like the TGA need to deal with software rather than simply bits of metal and plastic. It is unclear whether the TGA has the expertise or means to do so.

Solutions, not panic

The past decade has seen a succession of inquiries into the TGA, including the 2015 Sansom Review and 2012 Senate PIP Inquiry. Each has demonstrated that the TGA is not always keeping up with its task.Problems are ongoing: think defective joint implants, breast implants and vaginal mesh. But there are some potential paths towards improvement.AccountabilityOne solution is to ensure the TGA is more accountable.Currently, if someone wishes to bring a claim alleging a device was improperly permitted, the TGA has immunity from civil litigation about regulatory failure.Removal of immunity will force it to focus on outcomes. That can be reinforced by giving it independence from the Department of Health, making it report direct to Parliament and ensuring the openness emphasised by the Pearce Inquiry.Regulatory captureMedical products regulation in Australia has been a matter of penny wise, pound poor. The TGA is funded by fees from the manufacturers and distributors that it regulates, in addition to some government funding.It needs a discrete budget that recoups costs but is not dependent on companies that complain regulation is expensive. It needs enough resources to do its job well in the emerging age of the internet of things, including access to independent expertise regarding cybersecurity and devices.A device registerHow many devices have been implanted and how many removed? The lack of data about medical devices is a problem.The government has so far not embraced recommendations for a comprehensive device register, one allowing timely identification of what was implanted and by whom.

Read More: Vaginal mesh controversy shows collective failure of the TGA and Australia’s specialists

Such a register would provide a means for determining problems with devices or medical practice. We need timely, consistent reporting of problems on a mandatory basis, as well as recall and transparent investigation of what went wrong.Disclosure of interestsThe inquiry into vaginal mesh revealed the WA Branch of Australian Medical Association had a financial interest in a device that may have seriously affected numerous women.There must be full disclosure of such interests, with meaningful sanctions where disclosure has not been made. This requires action by the TGA, professional bodies and the government.

So, what about assassination by wireless pacemaker?

The cybersecurity of medical devices is a matter for everyone.We need the TGA to work with manufacturers, distributors and health professionals to mandate best practice. Should, for example, manufacturers and practitioners ensure that implants do not rely on default passwords that are easily crackable? What about access by emergency services?There is a fundamental need to develop and enforce a national safety standard regarding all wireless implants. For that we need thoughtful policy, not just headlines.Bruce Baer Arnold, Assistant Professor, School of Law, University of CanberraThis article was originally published on The Conversation. Read the original article.

Expert/s: Dr Bruce Baer Arnold

Drugs and devices, Infectious diseases, Vaccination

Videos

New pneumococcal 15-valent conjugate vaccine that includes coverage against serotype 3

In this Product Explainer, Public Health Physician and Infectious Diseases Epidemiologist Prof Paul Van Buynder explains the burden of pneumococcal disease in both children and adult population. He explains why PCV 15 has increased serotype coverage and why improved immunogenicity against serotype 3 is important both from a clinical and public health perspective (5 mins).

Expert/s: Prof Paul Van Buynder