Better on site deposition and , high anti-inflammatory effect , less systemic absorption, less oral thrush

Dear Mirna!

Thanks for your answer.:) My problem: if it has higher anti-inflammatory effect: why?, lower absorption- sure? and why: hydrophil/lipophil properities? esterification of the molecule? I think the deposition depend on the MMAD of aerosol, the formulation of the drug (MDI, DPI), the devices, and the inhalation-technic of patient.

Do You/ or somebody know a publication in this question? Or opinion? Paula

There is little to chose between inhaled corticosteroids and all act similarly. The important issues relate to whether they are a prodrug such as ciclesonide or beclomethasone (reduced adverse effects in the URT due to steroid activity being initiated only on reaching the lungs). Less thrush, hoarseness, systemic effects as a  result. More important is MMAD and flow velocity on inhalation since that determines penetrance into small airways (Ciclesonide, beclomethasone (QVAR). These have MMAD 1.1um and have been shown to require about half the ICS dose to achieve similar benefit to larger particle DPIs (about 27-64x larger aerodynamic mass/size). There are many available review articles and articles starting with Bill  Busse et al in the mid 1990s that have demonstrated this point. To further minimise URT adverse effects use of an MDI and valved holding chamber will reduce aerosol deposition in the URT and target peripheral airways. Better control of asthma has been achieved with small particle aerosols and low inspiratory flow (15-30L/min) than with the much larger DPI-generated aerosols. 

There are three ICS with fine particle size: (HFA) beclomethasone dipropionate (Qvar), ciclesonide (Alvesco), and flunisolide (Aerospan) Ciclesonide is a pro-drug that is converted in the airways into the active metabolite des-CIC, and is thought to have a reduced potential for local and systemic side effects. Due to the drug binding to protein with slow release, it is licensed for once daily use, which may improve adherence.

It is a common belief that the smaller the particle the better, as most particles with an MMAD < 1 mm are largely exhaled again, this is not true. Theoretically ICS particles within a size range of 1–3 mm would be optimal when inhaled with appropriate flow, volume,and a breath hold to at least partially reach all airway generations. In clinical practice, the superiority of smaller particles ICS (ciclesonide, HFA-beclomethasone) has NOT been demonstrated.

Smaller particle size may be of greater importance in young children because of 1-smaller airways, 2-higher breathing frequency,and 3-smaller tidal volume. On the other hand, an adequate breath hold may be more important when using ultrafine particles to decrease medication loss on exhalation.

Particles in the 1–3 mm range might be more effective than ICS with larger

particles. In some cases, small ICS particles may be superior to larger particles in improving FEV1 and bronchial hyperreactivity as measured with

methacholine

In general, ICS particles should not be too large or too small and they should be inhaled slowly and steadily. Beta 2-agonists appear to be to be more effective as larger particles in the 3-6 mm MMAD size range, which is appropriate given the location of smooth muscle around the airways. In general, Nebs, MDIs & DPIs are quite the same

Budesonide has more systemic absorption than either fluticasone or mometasone primarily due to absorption of the swallowed fraction.

There are many factors influencing the safety and efficacy of ICS. It is only possible to evaluate the drug in its entirety; the active ingredient, excipients and the delivery device.

Note that while BDP is a pro-drug, the metabolite, BMP is an active glucocorticoid as well. 

While all the ICS are similar it is a mistake to think they are the same. It requires a lot of effort to look at the details of systemic adverse events and relative efficacy but there have been some head to head studies that have been informative. A good starting point is 2007 NAEPP report because of its extensive bibliography.

WOW!!!  What great responses !  I can add little or nothing except say that despite the chemical differences in the steroid molecules and delivery devises there is no one ICS that is best for every patient. All of these drugs have been studied extensively and all have their Pros and Cons --as well as a group in each camp who thinks A is better than B than C .

In reality there are little differences if one looks at the "average"(what ever that means) patient. I think the important thing here is to look at each individual response (INDIVIDUALIZE) and look for out for those who are different --greater susceptibly to adverse effects and less positive effects ( not all asthma patients respond to Corticosteroids--(something quite often forgotten).

Yes compliance is a major problem in asthma--and most other disorders-so once a day ICS may be important but COST is also important !!  $300 a month for an ICS ?? --and please don't say the patient does pay for it--The Public Always Pays

Dear Collegues! Thanks for answers! If we speak about size of  particulates: There is a Chaos of the key-terms.Some parts of the aerosol-therapy got different tones in the last decade. These are the location of the inflammation in the airways, the technical applicability and the farmacological attributes of the medicine (can get to the therapical target-area), the stability and fineness of the aerosol (could be liquid or dust). The size of particles affects the aerodynamic properties of the drugs and its delivery to distal airways, named small airways(and this two is not the same). The advertisement-like autocratical-created terminological categories (with lot of overlaps in point of anatomy and medicine-aerosols) make it difficult to interpret the results.The medical terminology: Our fine particles are categorised in many peremptorily created groups,:small/ fine particle: 6→5→4,7→3→≈1μm (=extrafine=???ultrafine. )

But:THERE ISN'T ULTRAFINE INHALED AEROSOL MEDICINE. ULTRAFINE IS AN WELL DEFINIED AEROSOL, WITH MMAD under 100nanometer (0,1 micrometer).

---and the potential problem with "ultra fine particles" is that at some point they can reach the alveoli and act like a gas being absorbed into the blood stream with much more systemic adverse effects, So it "ain't so easy".

Once again for me despite various promoted--often heavily-attributes of the different Products it is very difficult to generalize the effects in individual patients.  However I currently I would use a smaller particle ICS because  inflammation is in both SMALL and Large airways---perhaps even more of an issue in Children. So if a patient is not doing well with Brand A which is a larger particle product and their inhalation technique is adequate before giving up on ICS's==I would give them a 4-6 week trial of a small particle ICS especially if their Mid Flow Rates are low. Why not???

Dear Paula

A lot of responses for a great question

In synthesis I agree with our colleague Doctor James Kemp: there is no one ICS that is best for every patient.

Two major factors influence the anti-inflammatory effect of ICS: the molecular/transcriptional factor and the pharmacokinetic factor. Our colleagues have underlined the importance of the particle size, ability of the patient to make a correct inhalation, and of course, the importance of observance. So I will focus my response on the “molecular” factor

First, it is important to remember that some ICS need a local transformation in order to be fully efficient (BMP in BDP and ciclenoside). To my knowledge, no extensive study have evaluated a possible variability of the corticosensibility mediated by a patient specific transformation of these drugs.

Second, the airway retention of ICS depends largely on their lipophilicity. Inhaled budesonide becomes highly lipophilic reversibly by the formation of esters acting as a reservoir of active BUD. Differences exist with others ICS (Drug Metab Dispos. 2007 Oct;35(10):1788-96). This may explain the long duration of action of Budesonide and the possibility of once-daily dosing.

Third, the transcriptional effect of ICS influences their anti-inflammatory effect. We have compared various ICS and demonstrated transcriptional differences (Am J Respir Crit Care Med. 2000 Jul;162(1):57-63. ; Clin Exp Allergy. 2003 Jul;33(7):895-901.). We have also observed (unpublished data) a prolonged transcriptional effect (more than 24 hours for bud or mometasone or fluticasone) after a only 5 minutes exposition of the cell-line to the drug. This may also explain the long duration of action of BUD/mometasones/fluticasone and the possibility of once-daily dosing independantly of the esterification of the molecule.

In conclusion:  the most important factor is probably… THE OBSERVANCE. The active participation of the patient in the choice of its treatment and the observance is probably more important than a greater anti-inflammatory effect of the molecule. The reason is probably that manufacturers of drugs are making remarkable efforts in the screening of molecules available to the patient.

Best regards

Dany

Dear Colleagues!

Many-many thanks evrybody for the usefull and interessting ansewrs. Paula

This has  been a very interesting series of comments most have been quite on target. However I fear that what when a study reports an advantage with an ICS --or other drugs--and this is marketed by the Pharma Company involved it may indeed have little or no effect on the great majority of patients--or at least 50% of them.

Has everyone forgotten the "Bell Shaped Curve". or the Mean response ?

In medicine one should never generalize. So to answer Paula's question--again.

" Does Budesonide have any specific properties vs the other inhaled corticosteroids ?"

MY ANSWER: Yes it does!---- but that does not mean it is the best ICS for all patients !!

...and when the ICS treat only the symptoms and not the cause, where are and why aren't alternative ways? But this is an other question.

Well the traditional thought is that ICS treat the cause( Airway Inflammation --However not all inflammation Mostly that seen with Type 2 eosinophilic inflammation which not all asthmatics have) and Beta 2 agonist especially the short acting ones treat the symptoms. Although they "treat the cause" they mostly reverse the result of the inflammation and do not " turn off" or modulate the basic driver of the process which are the Cytokines  IL-4/5 IL-13 and probably others. 

Look at the published results with anti-IL Biologics like Dupilumab . Instead of getting 20-30 % improvement in mild to moderate patients, these Biologics are getting twice the response in moderate to severe patients. We are about to enter a new era of treatment for this and many other diseases.

Exciting--but will be expensive

Unfortunately for all too many years all asthma was considered the same and if ICS did not work then you were not using enough. Finally the experts have started talking about the Heterogeneity of Asthma---and not treating it as if it is a deficiency of corticosteroids.I wonder why it took so long?? 

Thank you for your question, with marketing it is often hard to determine which product is 'best'. Most studies comparing ICS have been unblinded or have an inadequate design. Some products may present a higher risk of side effects in certain patients such as pneumonia in COPD patients. While at therapeutic equivalent doses there appears to be an equivalent clinical effect variations may exist with different delivery devices. An advantage of budesonide is it is registered as category B for pregnancy. A useful reference (although getting old) is : Kelly H. Comparison of Inhaled Corticosteroids: An Update. The Annals of Pharmacotherapy. 2009; 43(3): 519-527.

From a practical point of view: It's the ICS of choice for pregnant asthmatics due to its safety track record.  A specific property. 

More great points about Budesonide --a very fine ICS. However even with a Class B rating for Pregnancy I have never seen a report of an AE in pregnancy or in the newborn from any ICS---so I would ask the question are we getting something we don't need ?

We do not really think so;  our practical problem in India seems to be compliance issues in accepting long term ICS rather than merits of one vs the other among most if not all asthmatics.  We prefer bud plus formeterol in general.

The rapidity of action of formoterol in the  bud + formoterol combination increase the compliance....

Once again I am very interested in the comments from different physicians and  experiences in other countries--which I can assure you we have in the US .

However are we getting away from Dr Herke's question ? ":Has budesonide any specific properities versus the other (inhaled) corticosteroids?"

Dear collegues!

Thank for the stimulating answers. On the spur of the moment I promise to collect the properities of budesonide (not on a market specific way) and send this summary evrybody. Paula

Budesonide is the ICS of reference. Fluticasone propionate is also a "very good" ICS. For me (who has treated infants and astmatic chidren sinnce 1975, the availability of the beclomethasone dipropionate was a great step in the treatrment of asthma. With any ICS the possibility of a significant action to prevent the decline of the pulmonary function remain to be demonstrate, whatever the ICS used.

I agree entirely; this is what I said in an earlier message.  Curiously, I too have

been treating adult asthmatics since 1972 !  Compliance is the key to better 

asthma control.

I agree with Om Prakash.

(Apologies for my orthograph faults (last message) due to a "finger disability" !)

Our Colleague, Professor Dutau has writen:

"With any ICS the possibility of a significant action to prevent the decline of the pulmonary function remain to be demonstrate, whatever the ICS used".

This is a major question... in asthma, COPD and “ACOS” patients…

For COPD patients, Cochrane conclusion in 2012 was : Long-term use of ICS (more than six months) did not consistently reduce the rate of decline in forced expiratory volume in one second (FEV(1)) in COPD patients (generic inverse variance analysis: mean difference (MD) 5.80 mL/year with ICS over placebo, 95% confidence interval (CI) -0.28 to 11.88, 2333 participants; pooled means analysis: 6.88 mL/year, 95% CI 1.80 to 11.96, 4823 participants), although one major trial demonstrated a statistically significant difference.

For COPD patients, GOLD conclusions in 2015 is: regular treatment with GCi does not modify the long term decline of FEV1 nor mortality (evidence A).

For asthmatic patients, is it possible to have the same conclusions whatever is the inhaled steroid?

Very interesting citation. I agree. Thanks.

Our disputation was about an inhaled medicine with budesonide. But the molucule and its effect are different things. See below, so is shorter:)

I think now: that the main characteristic points of budesonide are:

1.It can mimic the naturel steroids in esterification and in protenbinding, so can use this double puffer system. Consenquense: it does not confuse by low doses and in optimal cases the naturel diurnal rhytm.

2. Lipase of budesonid oleat in airways works slowly, so the medicine (and not the single molecule) has a long halflife-time in the tissues of bronchii, but in other places not. This reduces the risk of systemic side-effects.

Two other questions come from this facts:

a) What happen in the lung of embryo,who's mother is treated with asthma? Facilitation of maturation?

b) What is the matter in gut by "topically use" without esterification or with a faster lipase-activity? How can budesonide topically and organ-specific be?

Paula

Research The way from molecule to effect of therapy

Good informations ! It is the eternal problem of theory and practice ...