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Brymonidyna na twarz - Tajemnicze Piękno Naturalnej Pielęgnacji
Discussion
In 2021, Ghaffari et al. reported a series of six cases found in the literature on the systemic side effects of the accidental oral or nasal ingestion of brimonidine eye drops in children, reported up to the end of 2019 [31], together with five additional new cases from personal observation. Their ages ranged between 9 days and 4 years.
Miosis may be a helpful sign when investigating brimonidine intoxication but should not be considered a must for confirming the diagnosis.
The duration of hypotonia may be variable. Ghaffari et al. report that in all of their cases, hypotonia lasted about twice the time needed for recovery to a normal level of consciousness [31].
At the most recent follow-up visit, 11 months after the reported event, the child was doing fine, her parents reported a series of typical age-related behaviors, and we found no evidence of a residual defect or alteration upon careful physical examination.
The brimonidine concentration in the plasma sample collected from our patient about ten hours after its accidental ingestion was 0.790 ng/mL. Thus, in our 8-month-old girl, plasma concentrations were about 13-fold higher than the maximum mean plasma concentration observed in adults. Of course, it has to be remarked that this is oral versus topical consumption.
This level was similar to that found in an infant with Peters anomaly being treated with ophthalmic drops containing 0.2% brimonidine. The young patient was brought to the emergency department, proving lethargic, hypotonic, hypothermic, and unresponsive to stimulation. These episodes were repeated five times during the hospitalization period. In this case, brimonidine concentrations were reported to be 1.459 ng/mL and 0.700 ng/mL in the plasma 0–3 and 6 h after instillation, respectively [19]. These elevated plasma levels, along with the resolution of symptoms following brimonidine withdrawal, indicated the drug as the possible cause of the reported intermittent coma episodes [19].
Biochemical Study
A total of 100 μL of plasma/urine study samples, calibrators, and QCs were added to 300 μL of IS working solution (acetonitrile containing IS 2 ng/mL for plasma sample processing and 100 ng/mL for urine sample processing). After centrifugation, supernatants were transferred into other tubes and then evaporated until dry. The residues were reconstituted with 100 μL of mobile phase and finally transferred into vials for UPLC-MS/MS analysis. Altogether, 10 μL of the sample was injected into the ion source. More details on the calibrator and quality control materials, sample preparation, and UPLC-MS/MS analysis are fully reported in the Supplementary Materials.
The UPLC/MS/MS analysis performed on the urine sample revealed 8.40 ng/mL brimonidine concentration levels, supporting the initial clinical suspicion. The chromatograph in Figure 2 clearly highlights the presence of brimonidine in the patient’s urine sample.
Chromatographic separation of (A) brimonidine (quantifier), (B) brimonidine (qualifier), and (C) internal standard brimonidine-d4 in urine sample of the study child.
The clinical suspicion was further supported by the analysis of the patient’s plasma sample with brimonidine concentration levels of 0.79 ng/mL, as shown in the chromatograph reported in Figure 3 .
Chromatographic separation of (A) brimonidine (quantifier), (B) brimonidine (qualifier), and (C) internal standard brimonidine-d4 in plasma sample of the study child.
DISCUSSION
We investigated whether topical brimonidine could delay the development of SCC. The hairless mouse model is the standard tool for evaluating the photocarcinogenicity of drugs and has been widely used (12, 16, 17, 18, 19, 20). We showed that topical 1% brimonidine cream applied before UVR exposure delayed SCC development in hairless mice. In contrast, applying brimonidine after UVR exposure did not significantly delay tumor development compared with mice in a UVR‐only treated control group. Therefore, the delay in SCC development observed in the mice administered 1% topical brimonidine cream before UVR exposure was most likely caused by a UVR absorption by the drug. Brimonidine can absorb light in the UVB wavelength range (280–315 nm), as shown by Bouvier et al. (12). However, there can be multiple reasons for a delay in photocarcinogenesis.
When 1% brimonidine was administered to the skin of hairless mice before UVR exposure (Group 1), the drug delayed the development of the first, second and third tumors relative to mice that received UVR alone (Group 4). The application of brimonidine three times per week, 3–4 h before UVR exposure and for 365 days mimics the routine use by patients of a cream or gel in the morning and later exposure to the sun during the day (20). Our results showed a significant difference in the timing of tumor development between mice in Groups 1 and 4, indicating that prior application of brimonidine may protect against UVR exposure and confirming previous results in hairless mice, which showed that brimonidine did not aggravate photocarcinogenesis (12).
However, when a lower concentration of brimonidine was applied before UVR, there was no delay in tumor growth (i.e. no significant difference in the timing of tumor development between mice in Groups 2 and 4). This result agrees with the data presented by Bouvier et al. (12), who concluded that initial tumor growth was dose‐dependent. These researchers showed that brimonidine was ineffective below a particular concentration (0.18%), suggesting that the minimal active concentration may be 0.18–1% (12). No vehicle controls groups were included in our study, which is a limitation of the study. However, we have previously investigated the same vehicle used in groups 1, 3 and 5 and it did not alter the time to tumor development or induce erythema in the same strain of mice. However, Bouvier et al. (12) demonstrated that the commercial gel‐formulation vehicle alone did not influence the carcinogenic response compared to UVR treatment in the absence of gel. Other studies, such as that by Fowler et al. (6), evaluated the optimal concentration, efficacy and safety of brimonidine gel for treating erythema in patients with rosacea and showed that the vehicle formulation did not aggravate erythema or other diseases. The vehicle of the in‐house cream formulation (without titanium dioxide) had no effect on the carcinogenic response (C. M. Lerche, unpublished data). This information supports our finding that 1% brimonidine cream has a protective effect against UVR.