(Oral) enoximone in asthma

Abstract

The Enoximone in status asthmaticus letter [1] referenced our case series from the Netherlands wherein intravenous enoximone (Perfan, Carinopharm, Germany) reversed status asthmaticus in eight patients [2]. SCHULZ et al. [1] end their letter with the statement that further research is called for; this correspondence is to indicate that research has been carried out and is still ongoing. Recently, SOBHY et al. [3] confirmed our case series with a successful clinical trial, which was performed in Egypt, using the phosphodiesterase (PDE)-3 inhibitor milrinone. We would like to report we are currently treating 12 children and 51 adults (outpatients) with oral enoximone (Perfan) in addition to standard therapy, in the context of investigational use, in search of effectiveness [4]. Enoximone very swiftly and markedly improved difficult-to-treat asthma, as well as reduced steroid and β 2-agonist drugs in 47 of the adult patients, and in 11 of the 12 children. Enoximone in oral form is used to reduce pulmonary arterial pressure by relaxing vascular smooth muscle and it has been used in paediatric post-operative heart failure since 2005 [5, 6]. Our average oral doses are 0.0625-0.125 mg•kg −1 , which is 1-6 mg per day for children and 5-15 mg per day for adults; some of them take the drug only two or three times per week. In the Netherlands physicians are allowed to treat their patients with drugs that are not indicated/registered for a particular disease, provided dosage, results and side-effects are closely monitored. We contacted the Dutch Inspection for Health Care and Youth regarding our add-on use of enoximone.

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia

“…These patients received a maximum oral daily dose of 25 mg enoximone in a customized fashion (i.e., once daily or less) without noticeable side effects. 16 At the currently applied dosing regimen, enoximone was well-tolerated on top of other medications and, as expected given no reported interactions or contraindications, no clinically relevant adverse events were noted.…”

“…In the presented cases, we applied even lower doses of enoximone based on our experience with oral enoximone in asthma patients (>80 patients and approximately 300 patient years) 16 in an ambulatory setting. These patients received a maximum oral daily dose of 25 mg enoximone in a customized fashion (i.e., once daily or less) without noticeable side effects.…”

“…In this emergency setting, enoximone was given (at much lower doses than marketed) within the scope of regular patient care and based on previous successful case reports … 5,6,16 including our own experience in another indication (asthma) with a similar pathophysiologyall in line with good clinical practice (GCP). No prior ethical consent (MEC or IRB) was required.…”

“…The algorithm for a safe, well-tolerated and effective dose and dosing regimen was based on our previous experience in near fatal asthma and status asthmaticus in the emergency department and on preoperative treatment of severe asthma patients. 5,6,16 In our COVID-19 patients with severe pneumonia, we used an intravenous bolus of 20 mg (0.25 mg/kg) enoximone followed by 10 mg/h (via perfusor) (0.125 mg/kg/h (i.e., approximately 2.1 mcg/kg/min)) for approximately 24-48 h, which is approximately 10-12-fold lower than the commonly applied (marketed) dose for cardiovascular indications (i.e., doses up to 2400 mg i.v./d).…”

New Avenues for Phosphodiesterase Inhibitors in Asthma

“…46 Also oral enoximone very quickly and significantly improved difficult-to-treat asthma, as well as reduced steroid and β 2 -agonist drugs in 47 out of 51 adult patients, and in 11 of the 12 children. 47 Preclinical data have shown that sildenafil, a selective PDE5 inhibitor that is used extensively in erectile dysfunction in males, inhibits the airway hypersensitivity and leukocyte influx in conscious guinea pigs 48 and could reduce airway inflammation and mucus production in rats. 49 Furthermore, sildenafil and tadalafil, another selective PDE5 inhibitor decreased pro-inflammatory cytokines in serum and BALF and inhibited oxidative and nitrosative stress in a rat model of bronchial asthma.…”