Topical Cysteamine Research Articles

Adherence to Cysteamine Therapy Among Patients Diagnosed with Cystinosis in Saudi Arabia: A Prospective Cohort Study.

Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the cellular lysosomes, causing damage to multiple organs. Due to challenges with the stringent cysteamine treatment regimen and side effects, adherence is often sub-optimal. This study aimed to assess the level of adherence to cysteamine therapy among cystinosis patients in Saudi Arabia and its impact on their quality of life. Electronic medical record data of 39 cystinosis patients from the Department of Nephrology at King Faisal Specialist Hospital and Research Center in Saudi Arabia were reviewed, and 25 patients were included in this study. Out of the 25 patients included in the final analysis, 64% (n = 16) were female. The mean age was 19.04 years. Almost all patients (23/25, 92%) were on oral IR cysteamine therapy, and 52% (13/25) were on topical cysteamine eye drop treatment. Of the 15 patients who responded to the Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire, only 4 (26.7%) were highly adherent to cysteamine therapy. Most of the respondents (7/15, 46.7%) showed a medium level of treatment adherence. Based on the medication possession ratio for oral cysteamine, only 6 out of 23 patients (26.1%) were found to be 96-100% adherent. For the cysteamine eye drops, only 5/13 patients (38.4%) were 76-95% adherent. The 36-Item Short Form Health Survey (SF-36) used to assess patients' health-related outcomes showed that their quality of life was affected in the domains of 'social functioning' and 'energy/fatigue.' Despite a small sample size, this study shows sub-optimal adherence to cysteamine treatment in patients from Saudi Arabia. The possible reasons for low treatment adherence could be a high frequency of administration and treatment-related side effects.

Importance of adherence to topical cysteamine in infantile ocular cystinosis: An illustrative case

Importance of adherence to topical cysteamine in infantile ocular cystinosis: An illustrative case

Analysis of tear film in cystinosis patients treated with topical viscous cysteamine hydrochloride (Cystadrops®)

PurposeThe aim of this study was to evaluate in vivo the tear film in infantile nephropathic cystinosis patients with corneal crystals treated with topical viscous cysteamine hydrochloride (Cystadrops®).MethodsTen eyes of five patients with nephropathic cystinosis aged from 10 to 35 years were included in this study. The patients were under treatment with viscous cysteamine hydrochloride formulation containing 3.8 mg/mL cysteamine (vCH 0.55%, equivalent to 0.55% CH; Cystadrops®; Recordati rare Diseases, Puteaux, France) to reduce corneal crystal density. Five age and sex matched individuals were randomly selected as control group. Tear osmolarity testing (TearLabTM) was performed to assess the in vivo osmolarity of patients under treatment and compared to control group values. Tear film break-up time (TBUT) and basic tear secretion (Schirmer test) were also assessed.ResultsMean tear osmolarity was 294.8 mOsms/L (±10.4), with a mean absolute difference of 1.85 mOsms/L (±2.13) between the eyes. There was no statistically significant difference between the osmolarity readings of cystinosis and the control group (294.8 ± 10.4 vs 299.4 ± 6.2mOsm/L, respectively; p = 0.39). The mean TBUT was 10.2 ± 0.83 s in the study group versus 10 ± 0.7 s in controls (p = 0.62). The mean Schirmer test score was 9.2 ± 0.83 mm in the patients versus 10.2 ± 0.83 mm in the controls (p = 0.14).ConclusionsThe TearLabTM osmolarity system test showed good reliability and precision in repeated measurements. This is the first report using the TearLab osmolarity system to assess tear film in patients with cystinosis treated with vCH 0.55%. TearLabTM examination showed that the use of vCH 0.55% drops does not determine alterations of the tear film quality.

Topical Stabilized Cysteamine as a New Treatment for Hyperpigmentation Disorders: Melasma, Post-Inflammatory Hyperpigmentation, and Lentigines.

Cysteamine is an aminothiol naturally present in cells of the human body as an antioxidant resulting from the degradation of Coenzyme A. Physiologically it is well distributed in mammalian tissues. Highly concentrated in human milk, cysteamine acts as an intrinsic antioxidant and is known for its protective role. Multiple studies now document that cysteamine is a potent skin depigmenting agent. Historically, its rapid oxidation and very offensive odor made it difficult for topical use until recently when stabilization of cysteamine was achieved. This has led to an acceptable galenical form for topical application. Since 2015, the efficacy, safety, and tolerability of stabilized cysteamine (st.Cys) has been demonstrated in multiple clinical studies, as well a case reports. Stabilized cysteamine has demonstrated significant effectiveness for the treatment of melasma by two double-blind randomized and vehicle control trials. Stabilized cysteamine (st.Cys) has shown to be as effective as well-known depigmenting therapies, including triple combination cream or tranexamic acid mesotherapy, with higher tolerability. A recent clinical trial has shown considerable efficacy of topical cysteamine for the treatment of senile lentigines, which are usually considered to be resistant to topical depigmenting agents. Topical stabilized cysteamine can be regarded to as one of the most potent treatments available for hyperpigmentation disorders in humans. J Drugs Dermatol. 2021;20(12): 1276-1279. doi:10.36849/JDD.6367.

Evaluation of the efficacy of cysteamine cream compared to hydroquinone in the treatment of melasma: A randomised, double-blinded trial.

Melasma is a commonly acquired disorder of hyperpigmentation that often poses a therapeutic challenge for dermatologists. Recently, cysteamine cream has shown promising results compared to placebo. This study aims to determine the efficacy of cysteamine cream compared to hydroquinone cream in the treatment of melasma. A randomised, double-blinded, single-centre trial was conducted in Victoria, Australia. 20 recruited participants were given either cysteamine cream or hydroquinone cream for 16weeks. The primary outcome measure was a change in the modified Melasma Area and Severity Index (mMASI). Quality of life at baseline and week 16 as well as standard digital photography at each follow-up visit was assessed as secondary outcome measures. At week 16, 14 participants completed the study with 5 participants in the cysteamine group and 9 patients in the hydroquinone group. In the intention to treat analysis, there was a 1.52±0.69 (21.3%) reduction in mMASI for the cysteamine group and a 2.96±1.15 (32%) reduction in the hydroquinone group. The difference between groups was not statistically significant (P=0.3). Hydroquinone cream was generally better tolerated that cysteamine cream. Our study suggests that topical cysteamine may have comparable efficacy to topical hydroquinone. Cysteamine thus provides a possible alternative to patients and clinicians who wish to avoid or rotate off topical hydroquinone. While side effects were more common for participants using cysteamine compared with hydroquinone, these were mild and reversible. Larger studies comparing cysteamine and hydroquinone are required to support these findings.

Efficacy and Safety of Topical Cysteamine in Corneal Cystinosis: A Systematic Review and Meta-Analysis

To evaluate safety and efficacy of topical cysteamine ophthalmic solution for corneal cystinosis. Seven databases were searched (PubMed, OVID, EMBASE, Web of Science, Cochrane Central, Google Scholar, and ClinicalTrials.gov) for relevant studies, using appropriate keywords. Comparative observational studies and randomized controlled trials comparing cysteamine with control or other formulations for treatment of corneal or ophthalmic cystinosis were included. Outcome measurements were improvement or response to therapy, change in corneal cystine crystal score (CCCS), invivo confocal microscopy score (IVCM), cystine crystal depth, contrast sensitivity (CS), photophobia score, and safety. Systematic review and meta-analysis. Seven studies were included. Compared to placebo and control, the cysteamine arm was better in terms of improvements and responses to therapy (2 studies showed a risk ratio [RR] of 16; 95% confidence interval [CI]: 2.30-111.37) and crystal density score (1 study showed a mean difference [MD] of-0.80; 95% CI:-1.56 to-0.04). No significant differences were observed in terms of improvement in CS (1 study showed an RR of 7.00; 95% CI: 0.47-103.27). Compared to cystamine, cysteamine showed benefits in terms of crystal density score (MD-0.94; 95% CI:-1.64 to-0.24). Compared to a newer formulation, the standard formulation (cysteamine [Cystaran]; 0.55% cysteamine hydrochloride+ benzalkonium chloride 0.01%) performed better in terms of decreasing CCCS. Another newer, viscous formulation, Cystadrops, performed better than the standard formulation in terms of change in CCCS, IVCM score, corneal crystal depth, and photophobia score; however, local adverse effects and blurring were higher in the group receiving Cystadrops. Conventional cysteamine (0.1% to 0.3%) performed better than placebo (control) in terms of response to therapy. In terms of decreasing corneal cystine density, cysteamine (0.55%) was better than cystamine (0.55%), and the viscous Cystadrops (0.55%) was better than the standard formulation (0.1%).

A comparative study of topical 5% cysteamine versus 4% hydroquinone in the treatment of facial melasma in women

To assess the efficacy and safety of topical 5% cysteamine versus 4% hydroquinone in the treatment of facial melasma in women. Topical 5% cysteamine is an antioxidant and tyrosinase inhibitor that has been shown to be effective in the treatment of melasma. However, to date, no study has compared the performance of topical cysteamine to hydroquinone for facial melasma. A quasi-randomized, multicenter, evaluator-blinded clinical trial was conducted on 40 women with facial melasma who were submitted to the nightly application of 5% cysteamine (CYS) or 4% hydroquinone (HQ) on hyperpigmented areas for 120days. Both groups were required to use tinted sunscreen (SPF 50; PPD 19). Subjects were assessed at the inclusion and after 60 and 120days of treatment for mMASI, MELASQoL, and the difference in colorimetric luminosity between melasma and the adjacent unaffected skin. The Global Aesthetic Improvement Scale was used to assess the difference in the appearance of the skin through standardized photographs. The mean reduction of the mMASI scores was 24% for CYS and 41% for HQ (P=0.015) at 60days, and 38% for CYS and 53% for HQ (P=0.017) at 120days. The photographic evaluation revealed up to 74% improvement for both groups, without statistically significant difference between them (P=0.087). The MELASQoL score showed a progressive decrease for both groups over time, despite the greater reduction for HQ after 120days (P=0.018). Colorimetric assessment disclosed progressive depigmenting in both groups, without statistically significant difference between them (P>0.160). No severe adverse effects were identified in either group. Erythema and burning were the most important local adverse effects with cysteamine, although their frequency did not differ between groups (P>0.170). Cysteamine proved to be safe, well-tolerated, and effective, despite its inferior performance to hydroquinone in decreasing mMASI and MELASQoL in the treatment of melasma.

Asymmetrical Ocular Manifestations of Nephropathic Cystinosis; A Case Report

Patient: Female, 22Final Diagnosis: Nephrogenic cystinosisSymptoms: Bilateral eye painMedication: —Clinical Procedure: —Specialty: OphthalmologyObjective:Rare co-existance of disease or pathologyBackground:Infantile nephropathic cystinosis is the most common and severe variant of cystinosis, which is a rare autosomal recessive condition related to a defect in the transportation of the protein cystine resulting in its deposition in various organs. Due to the rarity of this condition, only 1 case with extensive ocular involvement has been found in the English-language literature. Here, we report a second such case to highlight the significance of early diagnosis in avoiding devastating but preventable vision loss.Case Report:We describe the extensive asymmetrical ocular involvement in a 22-year-old woman who had nephropathic cystinosis since childhood. Despite frequent follow up and systemic and topical cysteamine therapy, she developed ocular complications, including increased intraocular pressure, uveitis, and retinal changes with complete loss of vision in her left eye. In addition, her general condition requires a renal transplant in the near future.Conclusions:Ophthalmologists should be aware of cystinosis and the sequalae of ocular involvement in this disease, despite its rarity. Identification of the earliest corneal deposits should not be overlooked, especially in the context of other systemic manifestations that are indicative of the nephropathic variant of cystinosis.

Efficacy of topical cysteamine in nephropathic cystinosis

PurposeThe aim of this study is to evaluate the efficacy of topical cysteamine 0.55% eye drops in the treatment of corneal cystine crystal deposits in patients with nephropathic cystinosis.MethodsThirty-two patients...

Synergistic Cysteamine Delivery Nanowafer as an Efficacious Treatment Modality for Corneal Cystinosis.

A synergy between the polymer biomaterial and drug plays an important role in enhancing the therapeutic efficacy, improving the drug stability, and minimizing the local immune responses in the development of drug delivery systems. Particularly, in the case of ocular drug delivery, the need for the development of synergistic drug delivery system becomes more pronounced because of the wet ocular mucosal surface and highly innervated cornea, which elicit a strong inflammatory response to the instilled drug formulations. This article presents the development of a synergistic cysteamine delivery nanowafer to treat corneal cystinosis. Corneal cystinosis is a rare metabolic disease that causes the accumulation of cystine crystals in the cornea resulting in corneal opacity and loss of vision. It is treated with topical cysteamine (Cys) eye drops that need to be instilled 6-12 times a day throughout the patient's life, which causes side effects such as eye pain, redness, and ocular inflammation. As a result, compliance and treatment outcomes are severely compromised. To surmount these issues, we have developed a clinically translatable Cys nanowafer (Cys-NW) that can be simply applied on the eye with a fingertip. During the course of the drug release, Cys-NW slowly dissolves and fades away. The in vivo studies in cystinosin knockout mice demonstrated twice the therapeutic efficacy of Cys-NW containing 10 μg of Cys administered once a day, compared to 44 μg of Cys as topical eye drops administered twice a day. Furthermore, Cys-NW stabilizes Cys for up to four months at room temperature compared to topical Cys eye drops that need to be frozen or refrigerated and still remain active for only 1 week. The Cys-NW, because of its enhanced therapeutic efficacy, safety profile, and extended drug stability at room temperature, can be rapidly translated to the clinic for human trials.

A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: The Cystadrops OCT-1 study

ObjectiveTo establish the safety and efficacy of a new gel formulation of cysteamine hydrochloride (CH) eye drops, for the treatment of corneal complications of nephropathic cystinosis. DesignOpen label dose response clinical trial. ParticipantsEight patients with infantile nephropathic cystinosis including 4 children, 3 adolescents, and 1 adult (mean age at inclusion, 12.1±4.6years) treated with CH 0.1% eye drops. InterventionPatients were treated, in both eyes, with the control CH 0.1% eye drop formulation on average 4 times daily for one month and then switched to Cystadrops® at the same dose frequency. Based on clinical ocular findings, the dose regimen was adapted at D30 and D90 in order to decrease the frequency of instillation. After D90, this dose frequency was maintained, except in cases of crystal density worsening. Patients had a follow-up visit every 6months during 48months. Main outcome measuresSafety assessment consisted of adverse event and serious adverse event monitoring and recording at each visit. For the efficacy study, the primary endpoint was the corneal cystine crystal density measured with an in vivo confocal microscopy (IVCM) score. ResultsAll patients completed the study. During the 4-year study period, neither serious adverse events nor significant adverse events related to the study drug were reported. After switching to Cystadrops®, the IVCM total score decreased from baseline to D90 by a mean of 28.6±17.5% (p<0.001). From D90 to M48, the IVCM total score remained stable and significantly decreased as compared to that at D1 despite a reduced dose regimen from D90. At M48, the mean IVCM total score was 8.13±4.15, decreased by a mean 29.9±26.29% from D1 (p=0.001), with a reduced number of instillations compared to that at D1. The IVCM total score and photophobia were significantly correlated (p=0.04). ConclusionThis study provides evidence that Cystadrops® gel is superior to the CH 0.1% formulation in terms of efficacy and has a good safety profile over a long follow-up period.

Growth hormone producing prolactinoma in juvenile cystinosis: a simple coincidence?

Juvenile cystinosis was diagnosed in a patient who presented with severe headache attacks and photophobia. Treatment with oral cysteamine and topical cysteamine eye drops was started. One-and-a-half years later, he developed unilateral gynecomastia and elevated prolactin and growth hormone levels. A pituitary macroprolactinoma was discovered and successfully treated with the dopamine agonist cabergoline. Increased serum growth hormone levels were attributed to enhanced growth hormone production by the prolactinoma and somatostatin inhibition by cysteamine. Although the occurrence of prolactinoma in this patient could be a simple coincidence, it might also be a rare yet unrecognised complication of cystinosis.

Successful use of topical cysteamine formulated from the oral preparation in a child with keratopathy secondary to cystinosis

To report the successful use of topical cysteamine formulated from the oral preparation in the treatment of severe photophobia from corneal crystal deposition in cystinosis. Interventional case report. Retrospective chart review. An 8-year-old boy with nephropathic cystinosis was experiencing debilitating and worsening photophobia from corneal crystal deposition. Because no parenteral cysteamine was available nationally, the oral capsule was used to formulate an ophthalmic preparation for compassionate use. After 8 months of topical application, the patient has marked improvement of his corneal disease, both subjectively and objectively. In situations of need, there is a role for the formulation of ophthalmic cysteamine from its oral preparation.

Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis.

As a result of successful renal transplantation, patients with nephropathic cystinosis are now living into adulthood. As these patients age, anterior segment ocular complications, other than deposition of corneal crystals, become more evident. With our experience with 172 patients followed up at the National Institutes of Health between 1976 and 2000, the prevalence of anterior segment complications in nephropathic cystinosis was determined. A cross-sectional examination of age-specific prevalence was performed with logistic regression analysis of prevalence change with age. Besides the corneal crystals apparent in all age groups, superficial punctate keratopathy, filamentary keratopathy, severe peripheral corneal neovascularization, band keratopathy, and posterior synechiae with iris thickening and transillumination were noted in the older age groups. The prevalence increased with age for each complication. As patients with cystinosis grow older, more severe ophthalmic manifestations become evident. It remains to be seen how the prevalence of these complications will be altered by early initiation of oral and topical cysteamine therapy.

A Randomized Clinical Trial of Topical Cysteamine Disulfide (Cystamine) versus Free Thiol (Cysteamine) in the Treatment of Corneal Cystine Crystals in Cystinosis

In nephropathic cystinosis, corneal cystine crystals cause severe photophobia and corneal erosions. Topical cysteamine dissolves these crystals, but cannot be marketed because it rapidly oxidizes to the disulfide form, cystamine, at room temperature. Since cystamine itself could be used commercially, we compared the efficacy of cystamine and cysteamine with respect to cystine crystal dissolution in a randomized, double-masked clinical trial. One eye each of 14 patients with cystinosis was randomized to either cystamine or cysteamine, 0.5%, with 0.01% benzalkonium chloride; the companion eye was treated with the alternate preparation. Corneal crystals were photographed and a density score was assigned to each slide based on 13 standard slides. After 8–20 months, 6 patients showed significant reduction of the corneal crystal score in only one eye. In each case, the improved eye was the cysteamine-treated eye. Theoretically, cysteamine should dissolve both intracellular and extracellular crystals, whereas cystamine should dissolve only intracellular crystals because it must first be reduced to the free thiol by the cytoplasmic-reducing environment. Hence, the lack of efficacy of the disulfide cystamine suggests that some corneal cystine crystals in cystinosis patients are extracellular, and that another form of stable, topical cysteamine must be developed for cystinosis patients.

Differences in action of topical and systemic cysteamine on gastric blood flow, gastric acid secretion and gastric ulceration in the rat

The effect of cysteamine on gastric blood flow and on the indomethacin-induced gastric mucosal damage was studied. In anesthetized rats, cysteamine (280 mg/kg) given subcutaneously (sc) decreased gastric blood flow measured by the laser Doppler flowmetry technique. In contrast, cysteamine (1–60 mg/ml) applied topically to the serosal surface of the stomach evoked a concentration-dependent and long-lasting increase in gastric blood flow. At 60 mg/ml, cysteamine increased blood flow by 166.8 ± 26.1% of predrug control value. Pretreatment with indomethacin (20 mg/kg, sc), intravenous (iv) atropine (1 mg/kg), propranolol (1 mg/kg, iv), combined H 1 and H 2-blockade or bilateral cervical vagotomy alone or combined with iv guanethidine (8 mg/kg), or pretreatment with the capsaicin analogue resiniferatoxin did not reduce the vasodilator response to cysteamine. The vasodilator response to topical capsaicin, was not reduced after sc cysteamine (280 mg/kg) pretreatment. In conscious pylorus-ligated rats, sc cysteamine (100 or 280 mg/kg) given simultaneously with indomethacin inhibited gastric acid output but had variable effects on the indomethacin-induced gastric mucosal damage. Cysteamine (100 or 280 mg/kg) administered sc 4 h prior to indomethacin enhanced gastric injury by sc indomethacin, but did not prevent the gastroprotective action of capsaicin. In contrast, orally administered cysteamine (60 mg/ml) reduced gastric injury induced by sc indomethacin plus intragastric HCl. These data provide the first evidence for the effect of cysteamine on gastric microcirculation in the rat and suggest a direct vasodilator effect for topical cysteamine. The microvascular effects of cysteamine are largely responsible for the different effects of this agent on experimental gastric injury.

The penetration of topical cysteamine into the human eye.

The penetration of cysteamine into human aqueous was measured to assess its suitability as a topical agent for the prevention of radiation-induced cataract. Cysteamine drops (0.5% and 1.0%) were administered preoperatively to cataract patients every half hour, for two, four, six or eight hours. Aqueous humor was collected at the start of surgery and assayed for total free thiol. There was no significant difference in the aqueous thiol level of any of the treatment groups compared with the controls. No side effects were observed.

1H-NMR spectroscopic study of cysteamine eyedrops

The efficiency of cysteamine eye drops in the treatment of cystinosis has been demonstrated in several studies: Corneal cystine crystals can be removed by topical cysteamine. Cysteamie 0.5% eye drops were superior to a 0.1% solution. It is not clear how fast cysteamine is oxidized to cystamine under the influence of atmospheric oxygen. Samples of a new bottled cysteamine 0.5% solution were analysed 1H-NMR-spectroscopically over a period of several weeks (AM 400/WB-NMR-instrument, Bruker/Karlsruhe; 400.15 MHz). Samples bottled in an argon atmosphere were compared to samples bottled without inert gas. Definite samples were opened four times a day (A). The remainder of the samples was stored closed (B). In sample A a 1:1 weight ratio between cysteamine and cystamine was reached after 38 days. In samples B cysteamine was not oxidized to cystamine. The initial amount of cystamine was something lower in samples with argon, but argon could not prevent the decrease of the cysteamine concentration in sample A. The preparation of cysteamine solution in an argon atmosphere is useful. One bottle can be used for about one week, if less than 10% of the oxidation product cystamine is accepted.

A randomised placebo-controlled trial of topical cysteamine therapy in patients with nephropathic cystinosis

Five patients with nephropathic cystinosis were evaluated to assess the ability of topical cysteamine to clear corneal cystine crystals. All patients were randomised to receive topical cysteamine 0.2% six times a day in one eye with normal saline in the other eye as a control. All five patients showed some improvement in visual symptoms (photophobia, blepharospasm and visual acuity) together with an improvement in corneal crystal density. Three of these also had an improvement in Snellen visual acuity and contrast sensitivity.

Clearance of corneal crystals in nephropathic cystinosis by topical cysteamine 0.5%.

A 2-year-old girl with nephropathic cystinosis was successfully treated with topical cysteamine 0.5% to one eye. Clearance of crystals from the treated cornea was virtually complete after three months. The possibilities and limitations of this form of treatment are discussed.