Chemistry and Life

Medicinal chemistry. Pharmacology. Toxicology. Environmental sciences.

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Can an old hallucinogen be a new antidepressant?

Ketamine is an anesthetic and sedative drug developed in the 1960s. It’s not widely used anymore, primarily because there are better options. Among its side effects are dissociative and hallucinogenic effects. Because of these effects, ketamine has also been used as recreational drug with the street name “Special K”.

Ketamine exerts its effects by modulating the neurotransmitter glutamate. Specifically, it blocks the function of a type of glutamate receptor in the brain called NMDA receptors.

In addition to its approved uses, ketamine has also been used off-label as an antidepressant, but its usefulness for this purpose is not well established. The only way to know for certain is to conduct well controlled clinical trials. It appears that Johnson & Johnson is trying to do exactly this (through its subsidiary Janssen). Like many organic molecules, ketamine can exist in either of two mirror images. Ketamine as used in medicine is an equal mixture of the two. J&J is investigating just one of them, named esketamine.

For a pharmaceutical company it is a bit of risk to take a drug that is abused recreationally into clinical trials. The path to regulatory approval won’t be easy. Although ketamine already has established medical uses and one might think that the existing approval for current uses would make approval for a new use simpler, but I’m not sure that’s going to be the case. Ketamine, when used as an anesthetic is given intravenously, but J&J is looking at nasal delivery. This could make a big difference. Intravenous drugs are generally given in a doctor’s office or hospital, while a nasal drug for depression will almost certainly be intended to be taken home by the patient where the potential for abuse is higher.

It will be interesting to see how this plays out.


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A contrarian view on the cost of sofosbuvir (Sovaldi)

There has been a lot written about the cost of Gilead’s new hepatitis C drug, sofosbuvir (Sovaldi). Most of the discussion has been highly critical of the price and Gilead’s stated justifications for it. Here is a contrarian view:

Each of these Hepatitis C pills cost $1,000. Thats actually a great deal.

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Chemical structure of alectinib

Chemical structure of alectinib

There is a new cancer drug on the market.  Alectinib just received its first regulatory approval for non-small cell lung cancer.  It was approved in Japan for a subset of such cancers, those that are known as ALK+ (anaplastic lymphoma kinase fusion gene-positive).

It’s interesting to me that this is a drug originally discovered by a Japanese company, Chugai Pharmaceutical (which is a subsidiary of Roche) and Japan is where its first approval was obtained.  I’ve seen this pattern before, where drugs discovered in a smaller country are first approved in that country.  It makes we wonder why that is the case.  The United States and Europe are the largest pharmaceutical markets and they are usually where approval is first sought and obtained – smaller markets generally follow later.

I think it points to the subjective nature of regulatory approval. Perhaps it is because of national pride.  Regulators may be pleased to see a “home-grown” drug and are therefore more favorably disposed towards it.  Or maybe there are influences from some form of regulatory capture, where the institutions that are doing the regulation draw their employees from the industry that is being regulated, introducing a bias.  Or maybe the company that developed the drug is just more familiar with the regulatory approval process in their own country than in other jurisdictions.

Regardless of the how it makes it to the market, it’s good to see another weapon in the arsenal for treating cancer.  Additional clinical trials are underway, and hopefully they will find that the drug will be able to benefit a broader range of cancer patients.

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Ceftolozane and tazobactam

Ceftolozane (top) and tazobactam (bottom)

Ceftolozane (top) and tazobactam (bottom)

In writing about antibiotics recently, I wanted to know more about what exactly the pharmaceutical industry is doing currently in terms of developing new antibiotics.  Ceftolozane appears to be one of the new drugs that is nearest getting FDA approval.

Ceftolozane (CXA-201) is an antibiotic currently under development by Cubist Pharmaceuticals.  According to Cubist, it is being targeted toward treatment of complicated urinary tract infections, complicated intra-abdominal infections, and ventilator-associated pneumonia. Ceftozolane is a cephalosporin antibiotic – a class of drugs for which there are already many available.  Cephalosporins are in the broader class known as beta-lactam antibiotics.  Some types of bacteria can limit the effectiveness of beta-lactam antibiotics through the action of an enzyme called beta-lactamase.  Basically, the bacteria break up the beta-lactam chemical group, destroying its effectiveness.

Ceftolozane is being studied for use in combination with tazobactam. Tazobactam has only weak antibiotic activity itself, but it acts as an inhibitor of beta-lactamase.  It prevents the bacteria from using the enzyme to resist beta-lactam antibiotics.  So the combination is more effective and broader in scope of activity than either of the two drugs alone.  Tazobactam is already used in combination with the antibiotic piperacillin.  The combination is marketed as Zosyn in the US.

Ceftolozane looks like it is well on the way to FDA approval and it will likely be useful certain types of infections.  But it doesn’t represent a breakthrough in fighting bacteria.  It is not a novel chemical class, it doesn’t have a novel mechanism of action, and the idea of combining it with a beta-lactamase inhibitor is already proven.


If the post-antibiotic era is imminent, why isn’t the pharmaceutical industry doing anything about it?

In a recent post, I discussed some recent reports warning of a looming “post-antibiotic era”, an epidemic of superbugs resitant to all antibiotics. In much of the reporting, there is an accompanying criticism of the pharmaceutical industry for not paying enough attention to the problem.  If there is a coming epidemic of antibiotic resistant bacteria, the pharmaceutical industry is the only entity capable of reversing the course.  Although academic labs, government organizations, and charities can all play a role in drug discovery and development, ultimately it can’t be done to any significant degree without involvement of the major pharmaceutical companies in some form.

But looking at the rate of regulatory approval for new antibiotics shows a steady decline over the last few decades (see the graph in this article for example).  Although pharmaceutical companies are not neglecting the problem of antibiotic resistance entirely – the new drug dalbavancin (Dalvance) for treating methicillin-resistant Staphylococcus aureus was approved just a few weeks ago, for example – the trend is clear.

Derek Lowe says the reason for this is that all the “low-hanging fruit” has been picked: If there ever was a field of drug discovery where the low-hanging fruit has been picked clean, it is antibiotic research. You have to use binoculars to convince yourself that there’s any more fruit up there at all. I wish that weren’t so, very much. But it is. Bacteria are hard to kill. But I don’t know if that’s really the issue.  The low-hanging fruit has been picked in nearly every area of drug research.  And in my estimation, developing a new antibiotic has got to be a much more tractable problem than developing a new drug for unmet medical needs such as Alzheimer’s disease where the pharmaceutical industry is investing heavily.

So why not do the same for antibiotics?

The only reasonable answer that I see is that the decision makers in the pharmaceutical industry don’t really believe that the post-antibiotic era is near, that there is no significant unmet medical need imminent in this area.  And that answer should hold even for the people that have the cynical view that pharmaceutical companies are only driven by greed.  Any company that comes up wih a drug to treat a widespread deadly superbug which no other drug can treat will have the opportunity to make a large amount of money.

The current state of the market for antibiotics is that there are numerous options currently available in a competitive environment. For most uses, low cost generic antibiotics with a long history of established medical use will continue to be widely used rather than expensive new medicines. The medical need for new antibiotics to treat resistant strains of bacteria is simply not great enough to entice pharmaceutical companies to invest in the expensive process of bringing a new antibiotic to market.  If new wonder drugs are developed to treat superbugs, they aren’t likely to be in high demand by doctors and patients.  Therefore, they will not be heavily prescribed, dramatically limiting profitability.


Is the post-antibiotic era really imminent?

Ever since I was an graduate student in the 1990s, I have heard warnings of an impending medical crisis – an epidemic of “superbugs” resitant to all antibiotics.  I remember being told by a seminar speaker that all of us who would end up working in the pharmaceutical industry would be working on discovering new antibiotics because that would be the top unmet medical need in the near future.  But for decades this crisis has always been a few years away, and if anything, the pharmaceutical industry is currently devoting less and less effort to developing new antibiotics.

The idea that this crisis is imminent seems to be becoming more mainstream lately, reaching a general news audience (here and here, for example).  The World Health Organization (WHO) recently released a report on the state of antimicrobial resistance worldwide, claiming “a post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is instead a very real possibility”.  And the warnings seem to be becoming ever more dire such as in this article headlined “Superbug threat as grave as climate change, say scientists“.

To be clear, there is no doubt that antibiotic resistance is becoming a greater medical reality every year.  The incidences of MRSA and other multi-drug resistant bacteria are more common.  But are we really at risk of returning to the state of medicine that existed before the discovery of penicillin, a “post-antibiotic era”?

When I look at the news stories, I see errors in the reporting that tend to exaggerate the problem.  One article says, “In some countries half of patients can’t be treated”, which isn’t true as written. (I think this is a misinterpretation of the finding that in some areas, half of the infections by a certain type of bacteria can’t be treated with one common class of antibiotics.)  Another article reports that 19000 people die in the United States each year due to infections by resistant bacteria, but that can be misleading without the context of how many of those people would have died even if the infection weren’t resistant (many people die each year due to infections by non-resistant bacteria, so a meaningful discussion would include a comparison between these two groups).  So my generally impression that the issue is being over-hyped in the news media.

But regardless of how serious the problem is, an organized response from the medical community worldwide is needed.  Local solutions will be insufficient.  So it’s good to see that an international organization like the WHO is making a serious effort at evaluating the problem and aiming to create a framework for a global response.  One aspect of the response will be to encourage judicious and appropriate use current antibiotics in order limit or slow down the development of resistance.   The other aspect will have to be development of new antibiotics, which I’ll write about shortly…