A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

This corrects the article DOI: 10.1038/cdd.2016.22.

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts 'on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

Prediction of acute pancreatitis risk based on PIP score in children with cystic fibrosis.

BACKGROUND: Currently no tools to predict risk of acute (AP) and recurrent pancreatitis (ARP) in children with cystic fibrosis (CF) are available. We assessed the prevalence of AP/ARP and tested the potential role of Pancreatic Insufficiency Prevalence (PIP) score in a cohort of children with CF. METHODS: We identified two groups of children, on the basis of presence/absence of AP/ARP, who were compared for age at diagnosis, clinical features, genotypes and sweat chloride level. PIP score was calculated for each patient. RESULTS: 10/167 (5.9%) experienced at least one episode of AP during follow up; 10/10 were pancreatic sufficient (PS). Patients with AP/ARP showed a PIP score ≤0.25 more frequently (6/10) than patients without AP/ARP. The odds ratio (95% CI) of developing pancreatitis was 4.54 (1.22-16.92) for patients with PIP <0.25 when compared with those who have a PIP score >0.25 (p 0.0151). PIP score was correlated with sweat chloride test (p < 0.01). CONCLUSION: PIP score, PS status and normal/borderline sweat chloride levels could be applied to predict pancreatitis development in children with CF. ARP could lead to pancreatic insufficiency.

Brand new SPINK1 and CFTR mutations in a child with acute recurrent pancreatitis: a case report.

We report a case of a 2,5 years old female, referred to our center for pancreatitis. Medical investigation revealed history of acute recurrent pancreatitis (ARP) since 1 year of age. Family history was negative for pancreatitis. Abdominal ultrasonography and magnetic resonance excluded both biliary tract stenosis and anatomic abnormalities. Calcium metabolic disorders, viral and bacterial infections were ruled out. Molecular sequencing of CFTR revealed heterozygosis for the mutation S1235R, a CFTR-related disorders associated mutation. Fecal elastase-1 (E1) was 529 µg/gr feces (normal value 200-500 µg/gr feces). No mutation of PRSS1 gene was detected but heterozygosity for p.Lys41Asn (c.123G>C), a new mutation of SPINK1 gene, was revealed. We speculate that the association of both SPINK1 and CFTR gene mutations may be responsible of ARP in our patient. Further studies need to better elucidate the role of genetic factors in ARP, as well as the influence of environmental factors.

[Experience in the surveillance of arteriovenous fistula in Verbania, Italy]. / Esperienza di Verbania nella sorveglianza delle fistole arterovenose.

One hundred forty-five patients are receiving renal replacement therapy at our center: 127 are on hemodialysis, 18 on peritoneal dialysis. From 2000 through 2005 a total of 215 arteriovenous fistulas (57% distal, 31% proximal, 12% prosthesis) were created. After some time we felt the necessity to design a vascular access surveillance system because the uremic population was increasingly constituted by aged people, including many diabetics and people suffering from hypertension with generalized vascular disease. The system comprised objective examination of the access at every dialysis session; kinetic Kt/V every 3 months; and a recirculation test (GIT) every 6 months. When there were anomalies in one of the above test results, color Doppler was performed. Detection of major stenosis with altered velocity parameters was a clear indication for angiography, possibly followed by angioplasty (PTA). In the indicated period, 15 patients underwent this procedure, and PTA was performed in all of them, often with placement of an endovascular stent. The results showed a survival of 12 months in 85% of patients and 18 months in 71% of patients. On the whole these data are comparable with others in the medical literature. The incidence of restenosis can be considered acceptable: it occurred in 3 cases out of 15 and could be corrected by PTA. In conclusion, PTA plus stent implantation is a valid method allowing quick and reliable correction of stenosis; a vascular access surveillance protocol and color Doppler imaging allow patient selection for angiography. PTA is to be considered an intermediate phase in stenosis correction before suggesting a new vascular access intervention to the patient.

Ibopamine treatment in chronic hypotony secondary to long-lasting uveitis. A case report.

PURPOSE: To assess the clinical efficacy of ibopamine eye drops in severe hypotony secondary to chronic progressive uveitis. METHODS: Case report. A 47-year-old man with a 37-year history of diffuse uveitis and severe refractory hypotony was treated with topical 2% ibopamine (Trazyl) six times a day. Intraocular pressure, visual acuity, visual field and side effects were recorded during 15 months of follow-up. RESULTS: IOP, visual acuity and visual field increased after four days of therapy and lasted for two months when the drug was suspended because of the onset of filamentous keratopathy. A new course of treatment with 2% ibopamine eye drops in a different solvent (BSS) resulted in a stable increase in IOP, VA and visual field, with no side effects in a follow-up of 13 months. CONCLUSIONS: Ibopamine 2% eye drops in BSS solvent seem effective in the treatment of uveitis-related hypotony.

Correlation between ocular hypertension induced by ibopamine and perimetric defect in primary open-angle glaucoma.

In 35 patients with bilateral primary open-angle glaucoma (POAG), with asymmetrical evolution of the neuropticopathy between the two eyes, we compared within each patient, the response to ibopamine and the perimetric defect. In 88% of cases (31/35 patients) the eye with the most severe perimetric defect had high intraocular pressure or a larger IOP increase after ibopamine. This result was highly significant at the sign test (P < 0.001). IOP and its increase after ibopamine significantly differed in the most and least affected eye, being higher in the eye with the most impaired visual field. Since ibopamine can be used to quantify the hydrodynamic impairment, which is thus presumably correlated to the perimetric defect. This study further confirms its importance in the development of glaucomatous damage.

Ibopamine in glaucoma diagnostics: a new pharmacological provocative test.

PURPOSE: Ibopamine is used when performing provocative tests, thanks to its pharmacological property of increasing ocular pressure in eyes with outflow system impairment. This study summarizes the latest results that we have achieved with reference to its clinical-diagnostic use. METHODS: 175 (250 eyes) POAG patients, 101 (190 eyes) glaucoma suspects with mild ocular hypertension, 39 (64 eyes) NTG patients and 163 (326 eyes) healthy volunteers underwent an ibopamine provocative test. Among the POAG and the glaucoma suspects, 49 (92 eyes) and 20 (38 eyes) patients were selected who, starting from the performing of ibopamine test, had at least one year of perimetric follow-up. These patients have been assessed for the perimetric defect progression in relation to the (negative or positive) response to ibopamine. RESULTS: the ibopamine test was positive for 92% of the glaucomatous patients, 61% of the glaucoma suspects, 52% of the NTG patients and 0% of the healthy volunteers. It was observed that 28% of the ibopamine-positive glaucoma suspects showed a perimetric deterioration during an average 2.5-year follow-up. No perimetric deterioration was found on ibopamine-negative glaucoma suspects (Fisher's exact test: p = 0.038). Among glaucomatous patients, 46% of the test-positive individuals showed a progressive trend of the perimetric defect, as against about 8% of glaucomatous test-negative patients (Fisher's exact test: p = 0.003). CONCLUSIONS: We believe that the ibopamine provocative test can be usefully applied especially to epidemiological screening studies to identify patients who might develop ocular hypertension or glaucoma and in the follow-up of glaucoma suspects, to identify individuals who have a greater risk of developing perimetric defects.

Increase in aqueous humor production following D1 receptors activation by means of ibopamine.

BACKGROUND: Topically administered 2% ibopamine (a dopaminergic agonist) induces a transitory ocular hypertension in 92% of patients with primary open-angle glaucoma and in 52% of patients with normal tension glaucoma. In normal eyes, ibopamine has no effect on IOP. PURPOSE: The aim of the present study was to verify, by means of fluorophotometric techniques, which hydrodynamic changes could be induced in normal and glaucomatous eyes, stimulating the D1 receptor with 2% ibopamine administered topically. In addiction, we wanted to evaluate if ibopamine could modify IOP before and after an experimentally induced outflow system impairment in rabbits. METHODS: In study 1 we performed a measurement of aqueous humor flow in 6 healthy volunteers and in 6 glaucomatous patients, before and after 2% ibopamine administration. In study 2 the alteration of outflow pathways was induced by means of Laminaria Digitata in 10 rabbits. RESULTS: After 2% ibopamine administration we found a significant increase in aqueous humor production, both in glaucomatous (P = 0.035) and normal eyes (P = 0.004). In rabbits, we found no significant change in IOP at basal conditions. After experimentally induced outflow system impairment by laminaria, we observed a marked increase in IOP (+ 13.5 mmHg SD 7.2; P < = 0.001) following ibopamine administration. CONCLUSIONS: These experimental data have a diagnostic value in glaucoma, since they show how an intraocular hypertensive response due to ibopamine in normotensive eyes is a sign of initial outflow impairment. Moreover, the possibility to increase the aqueous humor production sets new trends in the treatment of post surgical ocular hypotony.

Topical ibopamine and corticosteroids in the treatment of post-surgery ocular hypotony.

PURPOSE: The aim of the present preliminary study, performed on post-surgical hypotony, was the evaluation of the effects on ocular hypotony of the concomitant administration of ibopamine and corticosteroids. METHODS: 14 patients (11 males-3 females; mean age 47 years) with ocular hypotony following several vitroretinal surgical intervention in different districts, were enrolled. The inclusion criteria were: mean IOP during tonometric curve equal or lower than 6 mmHg, stable IOP for at least 60 days, ongoing treatment with 0.1% dexamethasone (4 times/day), successful surgical intervention, 2% ibopamine (4 times/day) was added to the corticosteroid therapy for 30-60 days. RESULTS: Before ibopamine administration, mean IOP was 4.07 mmHg SD 1.71. At the end of the treatment period, mean IOP increased by 89% in comparison to baseline values (+ 3.64 mmHg SD 5.57). This difference was statistically significant (paired t = 2.39; P = 0.03). One month after ibopamine-treatment discontinuation, mean IOP decreased to pre-treatment values (4.86 mmHg SD 3.50). CONCLUSIONS: The results of the present study, although preliminary, suggest the possibility of a future pharmacological treatment of ocular hypotony with ibopamine, whose rationale is based on the increase of aqueous humor production by stimulating the D1 dopaminergic receptor.

Dopamine, dopaminergic drugs and ocular hypertension.

The study refers to the clinical experiences performed with several D1 and D2 dopaminergic receptors agonists in 20 patients with high tension open angle glaucoma. The substances were administered topically as eye drops as well as an ocular eye bath. The parameter examined was intraocular pressure (IOP). The substances taken in consideration were: Dopamine, Ibopamine (dopamine analog), Fenoldopam and 3B90 (D1-receptor agonists) and Bromocriptine (dopaminergic agonist with higher affinity for D2 than for D1-receptors). It has been shown that all selective D1-receptors agonists induce a significant increase in IOP only in eyes with hydrodynamic disorders (p < 0.001). Such hypertensive effects could not be antagonized either by topically administered dopaminergic antagonists (Sulpiride, D2-receptors antagonist, and Haloperidol, non-selective dopaminergic antagonist) or by the pretreatment with the commonly used topical antiglaucomatous drugs. The only substance which proved able to inhibit the IOP increase induced by the D1-receptors agonists was the D1-selective antagonist SCH-23390, suggesting that IOP increase may be a result of a stimulation of the D1-receptors. The authors hypothesize that dopaminergic system may play a role in the regulation of aqueous humor hydrodynamics.

Therapeutic value of citicoline in the treatment of glaucoma (computerized and automated perimetric investigation).

The favourable neurotrophic effects obtained by means of the intramuscular administration of citicoline, one of the intermediate compounds of phospholipids, on the visual field of patients suffering from open-angle glaucoma are referred. The drug was administered at the dose of 1 gm for ten consecutive days. Visual field was examined by means of central computerized perimetry and automated perimetry. All patients had well controlled intraocular pressure through beta-blockers, but presented characteristic glaucomatous perimetric defects. It is suggested that citicoline might be administered as a useful complement to conventional hypotensive therapy, since it acts positively on the glaucomatous optic nerve damage.

Device for eliminating corneal light reflections during recording of lateral images with a slit lamp.

Corneal reflections produce defects in photographic sections of the lens taken with a slit-lamp biomicroscope for computerized densitometric analysis of cataract opacity. A simple and workable, adjustable antireflection device was built that can be easily adapted to photographic slit lamps, a common instrument in ophthalmology equipment. The slit lamp is a versatile tool for photographing structures in the anterior segment of the eye, particularly the lens. Corneal reflections are eliminated for angles between the light band and a photograph plane ranging from 20 degrees to 90 degrees, with the light band no greater than 0.5 mm and the corneal curvature about 7.6 to 7.9 mm. The device acts by blocking aberrant light rays from the light source that would otherwise be reflected by the mirrorlike surface of the cornea and enter the objective lens. Here we present a prototype designed for the Zeiss slit lamp.