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Saturday, July 20, 2013

Beta-blocker management of refractory hemoptysis in cystic fibrosis

 2013 Mar 28. [Epub ahead of print]

Beta-blocker management of refractory hemoptysis in cystic fibrosis: a novel treatment approach.


Department of Pediatric Pulmonary, Miller Children's Hospital, Long Beach/University of California, USA.



/objective: Recurrent hemoptysis is a debilitating complication of cystic fibrosis (CF) and likely results from mucosal erosions into abnormal bronchial blood vessels due to chronic respiratory infection. We hypothesize that the use of beta-blockade will decrease mean arterial pressure resulting in lower bronchial artery blood flow and, subsequently, decrease the frequency and severity of hemoptysis, rate of hospitalizations, and usage of intravenous antibiotics.


Retrospective chart review was performed on 12 CF patients with recurrent hemoptysis, aged 13-40 years old, along with a follow-up telephone survey to assess the effectiveness of beta-blockade for hemoptysis, tolerance of inhaled respiratory medications, activity tolerance, and potential adverse effects. A beta-blocker, specifically atenolol, was initiated in all subjects within 24 hours after experiencing recurrent hemoptysis episodes.


A majority of patients (72.7%) had complete cessation of hemoptysis. There were significant decreases in the frequency of hemoptysis (p = 0.02) and the amount of hemoptysis (p = 0.004). The rate of hospitalizations significantly decreased from 1.33 to 0.67 (p = 0.05) after initiation of atenolol. There was a trend toward statistical significance in the reduction of intravenous antibiotics use (p = 0.08). No statistical difference was found when comparing the pre- and post-treatment means of forced expiratory volume in 1-second (p = 0.59). Very minimal adverse effects were observed with only one patient reporting intermittent facial flushing.


Beta-blockade, particularly with atenolol, appears to successfully treat, if not resolve, recurrent hemoptysis refractory to conservative therapy in CF. Beta-blocker therapy appears to maintain an effective safety profile in CF.

Thursday, June 6, 2013

Von Willebrand's disease

I have just been diagnosed with Von Willebrand's disease (because one rare genetic illness isn't enough for me apparently) and I'm hoping my story might help others.

I got my first period on a class trip to Spain when I was 13 (you can't make this stuff up).

My period lasted 20 some odd days and was truly miserable. I got a few weeks off and Aunt Flo was back in town for another extended stay of 2+ weeks. This pattern repeated for a few months before I finally agreed to see an OBGYN to get checked out for any abnormalities.

Since I have CF, all weird things are often attributed to my genetic disease until proven otherwise - and my horrible periods were no exception. My ultrasounds of my uterus were normal, hormone levels were OK, so the doc, my family (yey to have family involved when you're 13 on the topic of periods.... I was mortified)  and I agreed to wait things out to see if my period "normalized."

Very soon after this agreement I threw up my hands in frustration as a then 14-year-old and demanded some sort of help. The OBGYN prescribed birth control pills and this solved everything. I was overjoyed to not have horrendous cramps or terrible fatigue from losing so much blood. Problem solved.

Fast forward to 27 years old, and I am diagnosed with my 1st superficial venous thrombosis in my left arm after I have a PICC for 2 weeks with abx. Not excited. I threw another superficial venous thrombosis in my right arm (later in 2009) with a PICC (I have this documented in my blog here btw) and naturally red flags go off in my head ; everyone knows estrogen makes you more prone to clots, right?

Fabulous. Off I go to a hematologist to get a work up just in case I'm in a hyper-coagulable state (for various reasons such as an undiagnosed Factor V Liden ) and everything turns out clean. I meet with a new OBGYN to understand my options for birth control and I'm presented with a few options: IUD's (Mirena which is progesterone-based, less clotting possibility; Copper with no hormones at all which can make periods worse), a progesterone pill, or depo privera. I liked the idea of localized (somewhat) hormones of progesterone, one less pill to take, yada yada with Mirena. So in goes the Mirena in December 2010 and off the birth control pill.

Periods begin to return to my 13 year old state- heavy, lasting looooong (2 weeks) for months. I am told by my OBGYN that it can take a few months for the Mirena to kick in. Summer 2011 arrives and periods are still horrendous. A re-visit to the OBGYN and I'm told that gosh, well, literature states in 3% of patients or so it can take a full 12 months for the Mirena to kick in. So I wait. And wait.

January 2012 rolls around and my Mirena has been in for 13 months and periods are still lasting too long and I'm an unhappy camper. I decide to switch OBGYN's to see if something else might be going on. February 2012 we decide on a transvaginal ultrasound to see if anything else might be causing excessive bleeding - fibroids, etc. Ultrasound looks normal but IUD looks slightly out of place ; it's hanging out in my cervix instead of in my uterus.

Feb 2012 I am diagnosed with CFRD so dealing with period issues kind of takes a back burner - CFRD and insulin is a steep learning curve and I need to focus on not destroying my lungs, kidneys, eyes, etc with high blood sugar.

May 2012 we decide, with this new OBGYN, to do a hysteroscopy In June 2012 to make sure nothing else is going on in my uterus that we couldn't see on the transvaginal ultrasound. We also decide to swap out my IUD for a shiny new IUD since who knows, maybe the IUD wasn't in the right place for the past 1.5 years and maybe this is why I'm having crazy bleeding.

Hysteroscopy goes great - nothing to report. No fibroids, no signs of endometriosis, uterine lining looks fine. Fantastic - hopefully this new IUD does the trick and takes away my miserable 1.5 year experience of loooooong periods. Mark in the calendar - June 2012 new IUD.

Our story now brings us to April 2013 - my periods are still lasting 3 weeks and are heavy. I'm exhausted, frustrated, angry and scared. My options for birth control are so limited and clearly Mirena isn't working.

I consult with my OBGYN and she suggests we try Depo. Ugh, that drug name just sends chills up my spine. I've heard so many bad things about the drug (extreme bone loss, infertility, unending hunger) that I am really hesitate to take this next step. I cancel my appointment to get my depo shot with my doc.

On a whim, I mention my struggles to a colleague and she suggests I visit an OBGYN in a fancy part of town who doesn't even take insurance. Great. I spend $1000+/ month on my healthcare as it is, so I'm not eager to drop a few hundreds of dollars on a doc I can't afford. But something tells me to do it.

This 3rd OBGYN in 3 years is very nice. She takes the time to listen to my history and she's eager to help. She suggests a few things that might be going on and recommends we run some blood tests. She also wants records of my blood clots to examine.

First on the list of tests is for a very rare genetic blood disorder. Less than 1% of the population has it and it's probable that I don't have it, but it's possible. She asks if I bleed a lot having teeth pulled (wisdom teeth) - not that I recall. Nose bleeds? Not really. Bruising easily? Why yes, I've definitely noticed that recently. Not my whole life, though. Just the past few years when I bump in to things I bleed easily. And with my insulin shots, I get a bruise very often at the injection site....I always assumed that was normal for shots. Nope. I bruise with my allergy shots in my arm too.... assumed it was normal. Not so much. Long periods are also a symptom of the disease - check.

The blood test would help us to see if the bruising and long periods were an indication of something being off.

Here are the results. 4 Hematologists and 4 OBGYN's later, I have von Willebrand Type I.

A hallmark of von Willebrand's is unexplained loooooong periods. And bruising.

So naturally we ask, why didn't I have long periods from age 14 to 27? Well, estrogen based birth control pills help mitigate the effects of von Willebrand's disease - so I had normal periods and didn't bruise as easily.

This also explains why I didn't have crazy bleeding issues during my many surgeries between 2000-2009 (hernia repair, gallbladder out, appendix out).... I was on an estrogen BC pill.

Great, so now what? Options to treat von Willebrand's are (1) resume estrogen based BC pills - The estrogen hormones present in birth control pills can boost levels of von Willebrand factor and factor VIII activity or (2) Desmopressin (DDAVP) that works by stimulating your body to release more von Willebrand factor already stored in the lining of your blood vessels.

You would imagine I would opt for DDAVP given my history of blood clots. Because both of my PICC-related blood clots were superficial in nature and not deep, my new hematologist feels comfortable putting me on estrogen birth control pills. So we're going to try that out for a few months and fingers crossed it helps!

Lastly, von Willebrand's is genetic (autosomal dominant, unlike CF which is autosomal recessive) which means there's a 99% chance I inherited my gene from one of my parents. I have informed my parents of the consequences of one of them having the disease (trouble during surgery, etc) but they have yet to get tested. Typical parents, right? Not sure about yours, but mine seem to have a lot less sense of urgency about their health than I do. Must be nice :)

I guess a lighter sense of urgency is the luxury of people in relatively good health or of those in denial. Which one my parents are - I think a little of both. 

I'll keep you posted on how my health goes with my new diagnosis and treatment. Wish me luck!

Saturday, January 26, 2013

Viagra a potentiator and corrector (in CF)

Viagra a potentiator and corrector (in CF)

JANUARY 22, 2013

The success of ivacaftor in targeting the CFTR defect in CF has re-focused attention on other agents that may potentiate or correct CFTR function. Among the candidates are the phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil (Viagra), vardenafil (Levitra) and taladafil (Cialis).

An initial study reported that sildenafil increased CFTR trafficking to the apical membrane in nasal epithelial cells obtained from CF patients (Dormer et al. Thorax 2005;60:55-9; free full text atwww.ncbi.nlm.nih.gov/pmc/articles/PMC1747155/pdf/v060p00055.pdf). Two animal studies subsequently found that PDE-5 inhibitors administered either by intraperitoneal injection or nebulization were able to stimulate chloride transport as shown by changes in nasal potential difference (NPD) (Lubamba et al. Am J Respir Crit Care Med2008;177:506-515, free full text at http://ajrccm.atsjournals.org/content/177/5/506.full.pdf+html; Lubamba et al.Eur Respir J 2011;37:72-78).

A recent German study has also found that sildenafil acts as a potentiator and corrector of wild-type and F508del CFTR channel activity, however, the high doses required may not be suitable in the treatment of CF (Leier et al. Cell Physiol Biochem 2012;29:775-790).

A new review of PDE-5 inhibitors suggests that inhaled vardenafil may be more appropriate due to its potency and longer duration of action (Noel et al. Front Pharmacol 2012;3:167; free full text atwww.ncbi.nlm.nih.gov/pmc/articles/PMC3444771/pdf/fphar-03-00167.pdf). Inhalation had a more rapid onset of action, appeared well tolerated and was not associated with clinically significant changes in heart rate or blood pressure in phase I testing (Berry et al. J Sex Med 2009; epublished July 28, 2009). Preliminary data suggest that vardenafil also reduces the expression of inflammatory cytokines in bronchoalveolar fluid (Lubamba et al. J Cyst Fibros 2012;11:266-273), but further study is needed.

Dr. Pearce Wilcox:
 Advances in technology have made it feasible for many laboratories to test compounds that might facilitate CFTR function. These referenced studies in cell systems and animal models illustrate the potential in F508del for a class of medications with already established clinical roles – PDE-5 inhibitors. Given that cAMP-dependent chloride conductance in CF epithelial cells is impaired, there is reason to believe  that modulating intracellular levels of cAMP could have beneficial therapeutic effects for patients with CF.  While an understanding of the mechanisms are limited, there is work to show a partial correction of the basic transepithelial ion transport abnormalities, and mitigation of the exaggerated inflammatory responses related to the F508del-CFTR protein. A wide dose safety margin of these compounds, based especially on work in pulmonary hypertension, has been shown. However, the study of Leier et al suggests that supraphysiologic levels may be needed to potentiate CFTR function. Consequently, the work outlined utilizing a nebulized PDE -5 inhibitor with favourable pharmacokinetics is an important next step. This impressive body of CF-related PDE-5 inhibitor research (outlined in detail in the review by Noel et al.) is the basis to move this class of medications into clinical research, facilitated by the approval and experience in other disorders. Indeed clinicaltrials.gov shows that Phase 1 and 2 studies in CF are already underway.