Is this shortage secondary to a lack of raw materials? Or perhaps pharmaceutical companies have little incentive to manufacture drugs with minuscule profit margins? Maybe politics is playing into it? Whatever the reason(s), our patients are ultimately paying the price.

The chief of ob/gyn at Ben Taub constantly drills one scenario into residents – never try IOL in a patient with an unfavorable cervix (according to the Bishop Score system).

So how do we make the cervix more favorable? Or in obstetrical (and culinary) jargon – “riper?” We typically try prostaglandins, but I came across something even cooler during my time on L&D – seaweed!

Yep, that’s right. Laminaria rods are inserted into the internal os of the cervix. They absorb the surrounding moisture and become larger in diameter causing the cervix to dilate in the process. This is a form of “mechanical dilation” as oppose to “chemical dilation” with prostaglandins.

…yeah…I’m probably the only one who thinks using seaweed in this manner is pretty cool. Oh well!

Oral vancomycin and metronidazole have routinely been used to treat this form of colitis, the former being better for more severe cases; however, as of May 27th, the FDA has approved a new antibiotic – Dificid (fidaxomicin). Dificid’s true beauty is in the fact that it, more or less, is selective for C. difficile thereby leaving healthy intestinal flora minimally disturbed. While Optimer Pharmaceuticals ascertains the “cure rate” of Dificid to be similar to that of vancomycin, it’s the recurrence rate they should rightfully herald as an achievement.

The following table shows the recurrence rate of C. diff in patients treated with fidaxomicin versus Vancocin© (vancomycin):

Source: Optimer Pharmaceuticals, Inc.

Cost will likely be an obstacle in the beginning, but it’s good to see a more efficacious drug being approved by the FDA for a relatively common and potentially fatal disease – Clostridium difficile colitis.

The attending physician was kind enough to walk us through a typical preparation. After receiving the patient’s informed consent, methohexital (a very short acting barbiturate) induces anesthesia and succinylcholine (a depolarizing neuromuscular junction blocker) globally relaxes muscular tone. These meds minimally affect a patient’s seizure threshold and are consequently good options. Sometimes patients are given caffeine to help them have a “better” seizure too. Electrodes then transmit the electric pulse to generate the seizure. Patients naturally wake themselves up due to the short half-life of the anesthetic. The overall procedure (assuming no complications) takes 5-10 minutes once the patient is prepped.

So how does jolting the brain help with depression? Frankly, scientists aren’t sure what the exact mechanism is, but it may deal with increased hippocampal neurogenesis – an outcome which is documented in murine cohorts receiving electroshock therapy. I guess it’s just another one of those things in medicine that we don’t understand but continue to use because it works.

Enter the RABBIT 2 Trial.¹

In a randomized, multicenter, prospective study of 130 patients split evenly into two cohorts of 65 individuals from the general medicine ward population, researchers attempted to assess the efficacy of SSI to a “basal-bolus” insulin regimen. As far as the demographics go, these patients ranged from 18 to 80 years of age and were previously treating their diabetes with either oral hypoglycemic drugs or solely dietary modifications. In other words, this is the first time the patients would be given insulin injections to control their DM. No patient follow-up information was included in the study.

Basal-Bolus Regimen

Daily insulin requirement based on admission BG: 0.4 units/kg for BG 140-200 mg/dL and 0.5 units/kg for 201 mg – 400 mg/dL

Half the required insulin would be glargine (a very long-acting insulin) given at the same time every day. The other half would be divided into 3 equal doses of glulisine (short-acting insulin) and given once before each of three meals. The glulisine was held if the patient could not eat. The glargine dose was increased or decreased by 20% if the premeal blood glucose was >150 mg/dL or after an episode of hypoglycemia (<70 mg/dL), respectively.

Sliding Scale Protocol

Patients received regular insulin four times a day for BG > 140 mg/dL. If patient couldn’t eat, insulin was given every six hours to avoid hypoglycemic event. If pre-meal BG >140 mg/dL, requirements were shifted to “Usual” or “Insulin Resistant” values. If the average BG was >240 mg/dL, patients were actually transitioned to the Basal-Bolus protocol and started on 0.5 units/kg. Seems like the researchers already knew which protocol was better going into the trial.

Insulin Scale

HbA1c was measured on admission and BGs were measured before each meal (every 6 hours if NPO). The whole point of the study was to keep patients below a BG of 140 mg/dL. The following table summarizes the important findings of the RABBIT 2 trial:

Given the two cohorts of DM patients with similar admission BGs, the basal-bolus regimen provided statistically significant improvement of hyperglycemic control (<140 mg/dL) over the SSI group.

1. “RAndomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2 Trial)” – http://care.diabetesjournals.org/content/early/2007/05/18/dc07-0295

I searched PubMed and Harrison’s Principles of Internal Medicine, but no where did I see a reference to a clinical trial which established the 100:40 mg ratio. Further research from multiple sources led to the following conclusion.

Aldactone is a relatively weak potassium-sparing diuretic which works in the cortical collecting tubule by inhibiting aldosterone receptors (typically responsible for the reabsorption of sodium with concurrent excretion of potassium into the urine). Lasix is a significantly more potent diuretic which works in the ascending Loop of Henle by inhibiting the Na-K-2Cl channel which can lead to secondary hypomagnesemia and hypocalcemia.

Using Aldactone in conjunction with Lasix essentially creates a diuretic effect with twice the efficacy of Lasix alone without having to worry about the side effects (namely hypocalcemia and hypokalemia) associated with a double dose of Lasix. In fact, since Aldactone is a potassium-sparing diuretic which works distal to Lasix in the nephron, it essentially offsets the hypokalemia.

Another way to think about this is that, in a normal kidney, more distal delivery of sodium leads to a rapid reabsorption of that sodium while sacrificing potassium (thanks to unopposed aldosterone). Aldactone counteracts this by blocking aldosterone receptors. Its been cited by many different sources I’ve read that the 100 mg Aldactone : 40 mg Lasix ratio maintains normokalemia while diuresing patients with volume overload.

Pretty nifty.

Human heart

For many years, Coumadin has been the oral anticoagulant of choice as prophylaxis against thrombus formation in conditions like atrial fibrillation; however, drug interactions with antibiotics, psychiatric drugs, and other drug classes have made dosing and monitoring the extent of warfarin-based anticoagulation troublesome. Pradaxa, a direct thrombin inhibitor, is the first oral anticoagulant approved by the US Food and Drug Administration in over fifty years. This new drug eliminates the need for conventional “INR monitoring” and is associated with significantly fewer drug interactions and dietary restrictions compared to Coumadin.

In the RE-LY® trial, over 18,000 patients from 44 countries (all with a history of A-fib on EKG at screening or within six months before entering the trial) were assigned into three groups: 110 mg Pradaxa b.i.d, 150 mg Pradaxa b.i.d, and warfarin (adjusted for therapeutic INR between 2.0 and 3.0). The primary outcome was a systemic embolism or stroke. Follow-ups were done, on average, two years later.

The results of this trial were strongly in Pradaxa’s favor. There were a reduction in the incidence of systemic emboli, stroke, major bleeding, and overall mortality in patients taking Pradaxa relative to those on Coumadin. The higher dose of Pradaxa (150 mg) was associated with a similar risk of major hemorrhage compared to Coumadin.¹

In spite of the success, a larger percentage of participants on Pradaxa discontinued their enrollment in the trial because of gastrointestinal symptoms like pain, vomiting, and diarrhea. Pradaxa is better absorbed at a low pH, so the tablets contain a tartaric acid core which may have caused the GI irritation.

Additional research is required to assess the long-term efficacy and safety for Pradaxa in other conditions where anticoagulation is indicated, but initial studies look promising in atrial fibrillation patients for prophylaxis against thrombotic events like strokes. With the United States’ healthcare system in a hotbed of fluctuation, the cost effectiveness of Pradaxa may be something to assess in more depth. Does the cost of warfarin (and necessary INR monitoring tests) make it more suitable for clinical use, or does the additional safety of Pradaxa justify its costs? This question and others will need to be further investigated as physicians learn more about the efficacy of Pradaxa in clinical practice.
_{1. “Dabigatran versus Warfarin in Patients with Atrial Fibrillation”      http://www.nejm.org/doi/full/10.1056/NEJMoa0905561}

I’ve never actually had a stance on this issue, but come to think of it, illegal drug use is becoming more prevalent in certain populations I’ll see as a physician. I’m not aware of any substantial “health benefits” attributed to, say, marijuana. In fact, the contrary is far more true. It seems that legalizing marijuana would make it more readily accessible and possibly lead to an explosion in drug-related illnesses, right?

What’s more interesting is the convoluted networks people must traverse to acquire illegal substances like marijuana in the current system. Drug cartels hold monopolies, significant amounts of money are being exchanged underhand, and most importantly, people are still able to satisfy their craving for cannabis. If it were legalized, would crime rates/deaths associated with drug exchange drop. Just a thought?

I honestly don’t know too much about this topic, but it’ll certainly have implications for the economy and healthcare system of the United States if marijuana becomes legalized. Also, has anyone else noticed how involved our government is with recreational substances? Remember, we are the country that had an amendment to the Constitution outlining the prohibition of alcohol… and then another amendment repealing it. I always found this hilarious: Oh, let’s make an amendment to stop the production, sale, and transportation of alcohol in this country. *Fifteen years later*… we were just kidding everyone. (enter the 21st amendment).

HCV’s major mode of transmission is blood-to-blood contact: tainted blood transfusions, IV drug usage with contaminated needles, and even tattoos/piercings can significantly increase the risk of contracting the virus. Current treatment for symptomatic patients is a combination of ribavirin and pegylated (increases the half-life) interferon; unfortunately, this cures HCV in less than 20% of affected patients.

Late stage clinical trials conducted by Vertex Pharmaceuticals Inc. have recently provided data showing a combination regimen with telaprevir increases the cure rate to ~65% (tripling the previous statistic!) As part of the trial’s parameters, the drug’s efficacy was assessed in HCV groups who:

• Had been successfully treated in the past but relapsed
• Had a partial response to some therapies
• Had virtually no response to therapies

The telaprevir combo regimen showed promise in all three study groups to varying degrees (patients who relapsed had the greatest improvement). With Merck also working on a new HCV treatment, the future looks bright for the 300,000 Americans (not to mention the countless others worldwide) who have the virus. The advances we continue to make in pharmacotherapy are just amazing.

We’re familiar with antibiotics working with the body’s immune system to destroy bacteria and resolve infections. In this case, antibiotics typically interact directly with the bacterial organism (halting protein synthesis, preventing cell wall formation, etc.) and the body has a chance to “catch up” with its immunological onslaught.

Disulfiram works in an interesting way. Since you can’t “target” chronic alcoholism, it’s mechanism is quite simple – if you’re caught drinking alcohol while on disulfiram, you’re going to regret it. Yes, it’s a drug therapy of intimidation.

Alcohol is metabolized by the liver to acetaldehyde (one of the main culprits of the “hangover”) which is subsequently metabolized to harmless acetic acid through acetaldehyde dehydrogenase. Disulfiram acts by inhibiting said enzyme and effectively raising the levels of acetaldehyde in the blood. The result? If you drink even a little alcohol, you’re going to have a miserably prolonged hangover – based on statistics, this has been a sufficient reason for chronic alcoholics to practice abstinence.