Alex Nowbar’s journal reviews—9 July 2021

Alex Nowbar reviews the latest research from the top medical journals

Will ranitidine make a comeback?

When ranitidine was taken out of circulation it left a fairly obvious void, as it was a popular drug for heartburn. But it was suspended for good reason. In 2019, a US citizen petition reported that the carcinogen N-nitrosodimethylamine (NDMA) was found in specific lots of ranitidine, and it proposed that ranitidine could convert to NDMA in the body. This was investigated by the US Food and Drug Administration, but the analysis had several general study limitations. In this new study, Florian and colleagues report on the effect of oral ranitidine on urinary excretion of NDMA. The study design was a randomised crossover of 18 healthy participants comparing 300 mg ranitidine with placebo and looking at 24 hour urinary excretion of NDMA. They tested a worst case scenario of people being able to convert more ranitidine to NDMA because of the presence of nitrites (through having a high nitrate diet from eating cured meat). The good news was that ranitidine did not increase NDMA in the urine. These data are reassuring for ranitidine, but they don’t necessarily mean that the drug will be back when other H2 antagonists have no such concerns.

JAMA doi:10.1001/jama.2021.9199

Physical punishment in children

Heilmann and colleagues performed “a narrative review of prospective studies.” If this were the title of a talk, I can picture the audience’s attention dropping to their phones. But this is a valid approach to systematically studying physical punishment and child outcomes, and it yielded useful results. Not all issues, especially public health ones, can be analysed in a more traditional manner like a meta-analysis. The main conclusion of this review was “documented compelling evidence that physical punishment is harmful to children’s development and wellbeing and has shown no evidence that it is beneficial.” This supports the principle of policies prohibiting physical punishment, but such policies may not address the drivers of parental behaviour, so more work is needed to develop interventions to actually improve child outcomes. The review also went into depth about common beliefs (for example, is it the child’s behavioural problems eliciting the physical punishment, or the other way round?). I highly recommend reading this review for its thoughtful approach to unpicking this issue of potential reverse causality.

Lancet doi:10.1016/S0140-6736(21)00582-1

Amyloidosis gene editing

I’m surprised to read a paper about the first six patients in a phase I, single arm study. Generally it is not good practice to report interim results. But it is wonderful news that the intravenous gene editing approach reported by Gillmore and colleagues was not unsafe and reduced the concentration of transthyretin protein in people with hereditary transthyretin amyloidosis. Evidence for efficacy of the CRISPR/Cas9 strategy for genetic disorders is growing, so get ready. I only hope that early promising results aren’t followed by neutral or unfavourable ones. It will also be important to see if the protein modifications translate into tangible clinical benefit. For example, after cardiomyopathy develops in amyloidosis, is it too late to meaningfully intervene with gene editing?

N Engl J Med doi:10.1056/NEJMoa2107454

Examining autophagy disorders

Autophagy (“self devouring”) is the process of cells degrading unwanted parts. Done right, it’s a crucial part of health. Done wrong, it can be fatal or, at the least, cause serious disease. A lot of work has been done in this area in animals. Collier and colleagues examine this process further in humans with a genetic, clinical, and neuroimaging analysis of five families who had members with developmental disorders. They found that defective autophagy underlies the profound neurodevelopmental impairment in 12 patients within these families through deleterious recessive variants in the ATG7 gene. This gene encodes a protein necessary for autophagy. This work advances our knowledge of the role of autophagy in human disease, especially in neural and musculoskeletal integrity. And with that comes the mildest twinkle of hope that gene therapy could one day be a therapeutic strategy for this series of patients or others with diseases related to impaired autophagy.

N Engl J Med doi:10.1056/NEJMoa1915722

Clarity on antibiotics for rectal chlamydia

This large Australian trial randomised men to 100 mg doxycycline twice a day for seven days or a single 1 g dose of azithromycin for asymptomatic rectal chlamydia. The primary endpoint of this 625 participant, double-blind trial was microbiological cure at four weeks. This was achieved in 20% fewer men in the azithromycin group compared with the doxycycline group—that is, the cure rate was 76% rather than 97%. This is critical evidence for the treatment of rectal chlamydia, as the two treatments were previously considered interchangeable. Clearly it is important to be using a doxycycline strategy. Gastrointestinal side effects such as diarrhoea were also more common in the azithromycin group.

N Engl J Med doi:10.1056/NEJMoa2031631

Alex Nowbar is a clinical research fellow at Imperial College London