Topical Ectoine: A Promising Molecule in the Upper Airways Inflammation—A Systematic Review

Table 1

Effects of included studies.

Authors	Study design	Patients distribution	Mean age (years)	Disease	Therapy	Efficacy parameters	Results	Side effects
Uwe Sonnemann et al.	Controlled, open label, noninterventional, multicenter	50 patients: ectoine group (25); beclomethasone group (25)	33.3	Allergic Rhinitis	Ectoine group: isotonic solution containing 2% ectoine, natural salt and water, one puff into the each nostril three times a day. Control group: 0.05 mg beclomethasone dipropionate spray, two puffs twice a day.; Both treatments were applied for two weeks.	Patients and physicians evaluated total nasal symptom score (TNSS), single symptoms score (nasal obstruction, rhinorrhea, nasal itching and sneezing), efficacy and tolerability of both treatments. Patients also completed a quality of life questionnaire.	Both treatments resulted in a significant decrease of TNSS values. Importantly, tolerability results were comparably good in both groups. Both treatments resulted in a clear improvement in the quality of life as assessed by a questionnaire answered at the beginning and at the end of the trial.	Three adverse events were reported: two cases of headache in the ectoine group (unlikely related to ectoine) and one case of “burning of nose” in the beclomethasone group (judged as probable).
Nina Werkhauser et al. First study	Controlled, noninterventional	48 patients: ectoine group (22); azelastine group (26)	35	Allergic Rhinitis	Ectoine group: one eye drop per eye and one puff of the nasal spray per nostril four times per day. Azelastine group: one eye drop per eye and one puff of the nasal spray per nostril twice per day.; The treatment period was one week.	Patients and physicians evaluated total nasal symptom score (TNSS) and total ocular symptom score (TOSS), efficacy and tolerability of both treatments; only physicians judged compliance.	TNSS and TOSS evaluated by physicians showed a significant reduction from baseline in both groups. TNSS and TOSS evaluated by patients decreased from baseline in both groups without significant difference. Patients and physicians assessment of efficacy and tolerability of both groups were similar without significant difference. Compliance was good in both groups, with no significant difference.	Eight adverse events: two cases of burning of eyes and itching of throat in the ectoine group, and six (four cases of burning of eyes, one case of nausea and one case of headache) occurred in the azelastine group. No serious adverse events occurred.
Nina Werkhauser et al. Second Study	Controlled, noninterventional, cross-over trial	50 patients: ectoine group (25);cromoglicic acid group (25)	34	Allergic Rhinitis	Ectoine group: nasal spray had to be applied at least 5 times per day. Cromoglicic acid group: spray had to be applied 4 times a day. After one week, patients swapped to the other treatment, for another week.	Patients and physicians evaluated total nasal symptom score (TNSS) and total ocular symptom score (TOSS), efficacy and tolerability of both treatments; only physicians judged compliance.	According to the physicians and patients judgment, the efficacy of both treatments was rated “good to satisfactory” without significant differences. Tolerability judged by physicians and patients was significantly better following a 7-day treatment with ectoine containing nasal spray in comparison to cromoglicic acid product. The compliance was assessed as very good by the physician, and values were not statistically different between groups.	No adverse events were observed during treatment with ectoine containing nasal spray. In contrast, 13 patients complained about a burning sensation during treatment with cromoglicic acid nasal spray. No serious adverse events occurred.
Andrea Eichel et al.	Prospective, observational, open-label, controlled, nonrandomized	66 patients: Ectoine group(48); herbal phytotherapeutic dragèet group (18)	Ectoine group (52.9); Control group (55.0)	Acute rhinosinusitis	Ectoine group: received ectoine (one or two puffs into each nostril several times a day). Control group: received one dragèet three times a day. The treatment lasts two weeks.	Physicians and patients recorded the Sinusitis Symptom Score (SSS) and adverse events. In addition physician performed nasal endoscopy and patients completed a sinusitis-specific health related quality of life (HRQL) questionnaire.	SSS evaluated by physicians and patients decreased significantly from baseline without significant differences. Nasal endoscopy and HRQL questionnaire scores improved from baseline in both groups but significant difference was recorded only in ectoine group.	One single adverse event in the ectoine group: burning sensation in the nose and secretion (assessed as ‘likely’). No serious adverse events occurred.
Uwe Sonnemann et al.	Prospective, open-label, noncontrolled, noninterventional	50 patients were treated with ectoine nasal spray (containing 0.5% ectoine).	40.12	Rhinitis sicca	During two weeks of treatment, patients were asked to use the nasal sprays at least five times daily.	Patients and physicians assessed the main nasal symptoms such as nasal obstruction and crusting of the nose and secondary nasal symptoms such as endonasal blood deposits, concomitant pharyngitis, cacosmia, rhinorrhea, exudate viscosity, and turbinate hyperplasia. In addition, they judged efficacy and tolerability of both products.	Nasal obstruction and nasal crust formations evaluated by physicians and patients improved significantly. Secondary symptoms evaluated by physicians significantly improved over the time in both studies, with the exception of rhinorrhea, which improved significantly only in the second study. From the analysis of the secondary symptoms conducted by patients, rhinorrhea significantly ameliorated. Efficacy and tolerability were judged as good by physicians and patients.	One adverse event (judged as unlikely). No serious adverse events occurred.
Uwe Sonnemann et al. Second trial	Prospective, open-label, noncontrolled, noninterventional	30 patients were treated with nasal spray with 0.5% ectoine and 1.0% dexpanthenol.	39.80	Rhinitis sicca	During two weeks of treatment, patients were asked to use the nasal sprays at least five times daily.	Patients and physicians assessed the main nasal symptoms such as nasal obstruction and crusting of the nose and secondary nasal symptoms such as endonasal blood deposits, concomitant pharyngitis, cacosmia, rhinorrhea, exudate viscosity, and turbinate hyperplasia. In addition, they judged efficacy and tolerability of both products.	Nasal obstruction and nasal crust formations evaluated by physicians and patients improved significantly. Secondary symptoms evaluated by physicians significantly improved over the time in both studies, with the exception of rhinorrhea, which improved significantly only in the second study. From the analysis of the secondary symptoms conducted by patients a significant reduction for bleeding, cacosmia, and exudate viscosity was also observed. Efficacy and tolerability were judged as good by physicians and patients.	One adverse event (judged as unlikely). No serious adverse; events occurred.
Müller D et al.	Prospective, controlled observational, nonrandomized	95 patients: ectoine oral spray (64); control group (31)	Ectoine oral spray (50.53 ± 18.39); control group (47.1 ± 19.87)	Acute pharyngitis and/or laryngitis	Ectoine oral spray: one to two puffs several times a day. Control group: one to two lozenges up to six times a day. The treatment lasts one week.	At all follow-up visits, physicians and patients evaluated hoarseness, swallowing difficulties, pharyngitis symptom score, tolerability, and efficacy.	Ectoine oral spray guaranteed an earlier improvement of hoarseness, swallowing difficulties and pharyngitis symptom score than control group without statistical differences. Ectoine oral spray showed higher efficacy than control group, as judged by physicians and patients recording a statistical significance only in the patient’s evaluation. Both physicians and patients rated the tolerability of the spray and the lozenges as ‘‘good’’ to ‘‘very good.’’	In the ectoine group five adverse events: three were unlikely to be related, one was unrelated, and one was the relationship to the treatment medication that could not be evaluated. In the control group, one adverse event, which was unlikely to be related. No serious adverse event was reported.
Dao VA et al.	Prospective, active- controlled clinical study	90 patients: ectoine group (35), hyaluronic acid group (35) and hypertonic saline gargle (20).	Ectoine group (33.4 years), hyaluronic acid group (33.7 years), saline gargle group (49.4 years)	Acute pharyngitis	Ectoine group: 1-2 lozenges every 3 h or as needed; Hyaluronic acid group: one or two lozenges every 2-3 hands up to six times daily if necessary; Hypertonic saline gargle group: 3-5 times daily. All treatment lasted 7 days.	Physicians and patients assessed primary variables (pain on swallowing, urge to cough, and hoarseness), secondary variables (dry mouth and throat, reddening of the oropharynx, reddening of the larynx, burning sensation in the throat, and patient’s general health condition), effectiveness, tolerability and compliance.	Primary variables significantly decreased in all three groups from baseline. The reductions were significantly greater in ectoine and hyaluronic acid groups than saline gargle group. Ectoine was more effective than hyaluronic acid in ameliorating the reddening of the larynx. Ectoine was significantly more effective than saline gargle in improving general health condition. Effectiveness evaluation showed a greater improvement in ectoine and hyaluronic acid groups than saline gargle group. The tolerability of ectoine was better than hyaluronic acid reaching significance only in the physicians’ evaluation. Physicians' assessment of compliance showed significantly better value in ectoine group than hyaluronic acid group while patients’ evaluation only highlighted that both lozenges were significantly better than the saline gargle.	No serious adverse event was reported.