This drug class is included in the Papich Formulary section, and a strength of evidence study is discussed in the pressbook.

If you were just scanning the executive summary I hope you would identify this as something you wanted to follow up in the actual study write-up section.

Does this seem very strange to anyone else? (but apparently not all that strange to the FDA!)

Speculate on why you think that there is a faster onset time?

Kind of an interesting study design. All we want is to be not worse than dexmed. alone, but we want to be superior in HR adverse effects. Also interesting that they did not want to be superior in BP adverse effects.

Do any of these potential adverse effects give you cause for concern at a level that you would either not use the drug or would counsel the client about their possible occurrence?

How does the placebo effect of the study veterinarians compare to that of the client-assessed placebo effect? Give me one example using numbers from the data to justify your response

OK, this is an important point. In our last FOIS on Zorbium, the study was referred to as "Masked" (aka Blinded). Here it is referred to as "Double-masked". What's up. Single blinding means that the patient (here the client) does not know whether they are taking the treatment or the placebo. In double-blinding neither the patient NOR the healthcare provider (here the vet) knows whether the patient is getting the treatment or the placebo.

See explanation above for how the monoclonal IgG is produced, and remember that this is a PROTEIN, and proteins have the potential to be immunogenic (much more-so than small chemical molecules . Immune activation caused by therapeutic monoclonal antibodies is a real problem, so the regulators want assurance that this new drug will not do that.

Pretty good subject numbers in this study

Very important. Their primary outcome is their definition of success in a patient. This is their definition of success in therapy. Do you agree? Is this a reasonable definition of success?

Ooooh! Sound familiar?

Not essential

Hmmmm in the world of scientifically guided evidence-based medicine, what exactly does "...were slightly lower (better)...mean?????

I like this, not all studies use veterinary assessment of response in their drug approval studies, and you can't in every kind of study (e.g. for anti-epileptics, you have to rely on client reporting of seizure activity).

What do you think about mentioning BOTH the non-statistically significant results AND the significant results?

See the CSOM example and explanation in the Pressbook chapter

What do you think about these inclusion criteria? Do the investigators want to enrich for cats on the low severity side? ... high severity side? ... a broad mixture of severities?

Key point for mechanism of action. NGF is a bad actor in amplifying pain and developing neuropathic pain. Like all agonists it specifically binds its receptor....except when it has a big honking semi-trailer stuck to it (the monoclonal anti-NGF antibody)!

This is a typical IgG molecule, with a couple of twists. 1. It was constructed in a lab by tricking mouse plasma cells that had been genetically manipulated. 2. The amino acid sequence was altered to more closely resemble the amino acid sequence of cat IgG. If you don't do this then the cat immune system will recognize the IgG as foreign and an immune attack gets launched.<br /> 3. The tricked plasma cells have been made cancerous, handy for manufacturing scale IgG production because the little antibody factories never stop growing/multiplying

OK, let's break down these terms: * multicenter: the study was conducted studying animals at multiple clinics/locations * prospective: study subjects are enrolled and followed BEFORE the disease or the outcome is observed (in this case the painful procedure/analgesic response. Prospective studies tend to be less prone to bias, compared to retrospective studies (like evaluating historical patient records of prior disase/treatment/outcome). * randomized: enrolled subjects are assigned to treatment or control groups randomly. Randomization can be an effective way to minimize intentional or unintentional bias in a study. For example, in a non-randomized study an investigator might (intentionally or unintentionally) place all of the younger subjects in the control group and the older subjects in the treatment group. Now you have two things that could contribute to a difference between controls and treatments, the actual treatment AND AGE. So if there was an improvement in the treatment group, which thing did it, treatment or age? Randomization reduces the occurrence of biases like that. * masked : this is also called blinded. In masking, one or more categories of study workers are blinded as to whether subjects are in the treatment group or the control group. I'd have to look at the full experimental write-up to know exactly who was blinded, but at a minimum the study workers assessing the analgesia should be blinded as to whether they are observing a treatment, or a control animal. This can be complicated! A vehicle control cat is unlikely to be dysphoric/euphoric, so if I am a study worker and I see a dysphoric cat, I will likely be biased to assume that it has been treated with drug, and that could in turn bias my assessment of its pain. * vehicle control : this is a form of placebo control. the treatment group gets vehicle+drug, the control group gets only vehicle. You will also read about "active control". In this case it is an intramuscular injection of bupe. This allows a comparison between all the things that can interfere with transdermal absorption, and an administration of bupe that bypasses the vagaries of transdermal absorption and lets the investigators know what a more reliably absorbed, roughly equivalent dose, is capable of. Placebo controls and vehicle controls are also related to masking/blinding. In the ideal world, almost no one should know whether a patient got the control treatment or the test treatment, until the study is completed and the data analyzed. This reduces bias in assessing the effect of the treatment. * pilot : a pilot study is an early study, often used to explore dose, timing, effectiveness in a smaller number of animals to aid in designing a larger subsequent study.

Remember, the two basic things that FDA requires for approval are 1) actual evidence that establishes the drug is an effective treatment for the specific indications in the application (in this case post operative analgesia in cats) and 2) typical use of the drug is unlikely to cause injury that is disproportionate to the risk that the disease presents. For example, most anticancer drugs may cause injury, but the diseases that they treat have a much greater risk of injury if left untreated. But there would be a much higher expectation of safety in a drug to treat kennel cough, a disease which is rarely fatal and often self-limiting. So here, in this data we'll see studies designed to provide evidence of effectiveness, and studies designed to provide evidence of safety.

This drug is not exactly an earth-shaking discovery. "BuTrans", from the notorious Purdue Pharma (in a legal settlement, Purdue Pharma agreed to disband as a business) was FDA approved for humans in 1981, is a transdermal buprenorphine patch.

Beyond our scope, don't worry about this.

Inclusion and Exclusion criteria are important! Remember, you are trying to keep the treatment group and control group as similar to each other as possible.

To me, the executive summary (not sure why they call it that!) seems to be pretty dialed-down for a non technical audience. This is a great skill to get better at, although at points the basic language can get a bit confusing

This concept is called dose proportionality, and it is a really handy thing to know. What they are saying here is that beyond a dose of 30mg/cat you lose dose proportionality. This implies that below that dose, if you double the dose you should see approximately a doubling of plasma concentration--That's dose proportionality!

This is a nice & clear explanation of "flip-flop kinetics"! Far more common is the situation in which absorption is fast, compared to the slower elimination. In that far more common scenario, half-life (aka terminal half-life) is driven by clearance. Here, the rate of absorption is so slow that whatever drug is absorbed is quickly distributed and cleared (but of course during that process some drug gets to its CNS targets and binds (tightly!) to them.

Not surprising since bupe is really, really lipophilic.

this is an example where oversimplification distorts the facts. "bind as strongly" is not accurate, and it disagrees with "high binding affinity" in the previous paragraph. Bupe does bind with very high affinity to the mu opioid receptor. It is a partial agonist because that tight binding is not capable of causing the conformational change in the receptor that is necessary to produce a maximal receptor response. The ability to fully activate a receptor is not a function of the tightness of binding (if that was the case naloxone, which also binds tightly, would be a full agonist). It is a function of whether the binding induces the 3-d changes in the receptor that cause it to signal its activation to the interior of the cell.

For Cephalosporins, focus on generations 1 and 3/4. Monobactams and Carbapenems will not be a focus of testing in this session.

For these antibiotics you will not be tested on which ribosomal subunit the drug binds to, or what it specifically does to impair protein synthesis in the bacteria.

Not a focus for this class session

The fatal, irreversible, aplastic anemia has not been observed in animals.

Don't get hung up on the "30S" type names. Just an arbitrary system that refers to relative mass of the subunit.

I won't test you on structure, this is just for you to see that the lactam categories are structurally related, which makes sense because they all need to "fit" into the transpeptidases (PBBs) to inhibit them!

So, compared to lactams that only block transpeptidation (cross-linking glycosyl groups), vancomycin blocks this, AND transglycosylation (the basic incorporation of the glycosyl groups into the structure)

MRSA An example of bacterial strain(s) that has a variant gene encoding a variant PBB protein, conferring resistance to nearly all lactam antibiotics.

You only have to focus on the classes/drugs discussed below in the text

But don't forget, for many drugs the risk and severity of adverse effects is also related to peak plasma concentration!

meaning treating a bacterial infection WITHOUT having performed culture/susceptibility testing to guide antibiotic therapy.

For a patient with a bacterial infection and a severely impaired immune system, which do you think would be preferable, a bacteriostatic antibiotic or a bactericidal antibiotic? (understanding that immune system status is not THE ONLY factor in the decision!)

I was talking with a TBL group yesterday about how ivermectin is all over the news. We are not going to devote class time to that phenomenon, but if you want to discuss it out of class I'm happy to!

I don't actually know anybody who pushes the idea of "only ever use System 2"!!! That just doesn't make sense when you know how all humans operate.

The drug safety literature has plenty of examples of this in human medicine, kind of scary.