N-acetylcysteine in chronic blepharitis

tube without topical anesthesia and without irritating the conjunc- tiva. We then spread it onto a clean microscope slide and let it dry at room temperature. The collected samples were inspected with a light microscope at a magnification of 150 and 400 times the actual size. The mucous crystallization pattern was classified into four groups5,6 (Fig. 1A–D):

Type 1: Regular, frequent branching ferning without spaces be- tween leaves; ferning is expected in healthy tear sinema.

Type 2: Smaller ferning pattern showing less branching and ex- isting space between leaves.

Type 3: Smaller leaves, little or almost no branching, broad spaces attracting attention.

Type 4: No crystallization or very loose. Mucus accumulation and shapeless structure are attracting attention.

The Schirmer-1 test increase rate (the difference between the first and last results) in the therapy group was compared with the increase rate in the control group using a Student t test. The FBUT increase rate in the therapy group was compared with the increase rate in the control group using a Mann-Whitney U test. The mu- cous fern test increase rate in the therapy group was compared with the increase rate in the control group using a Student t test (Tables 1 and 2).

RESULTS

The Schirmer-1 test results showed a en az of 1 mm and a maximum of 50 mm for the therapy group. In this group, the Schirmer value increased in 23 eyes, decreased in 17 eyes, and remained the same in three eyes. For control patients, the Schirmer-1 test results showed a asgarî of 1 mm and a maxi- mum of 45 mm. In this group, Schirmer values increased in 10 eyes, decreased in 23 eyes, and remained the same in two eyes. The average Schirmer-1 first and last values were 15.53 and 16.02 mm, respectively, in the therapy group and 24.22 and 16.8 mm, respectively in the control group. The average Schirmer increase rate (difference between first and last results) was 0.534 (± 8.993 standard error) in the therapy group and −7.5(± 10.522 standard error) in the control group. Considering these rates, there was a significant difference between the groups (t 3.660, p < 0.0005) (Figure 2).

In the therapy group, FBUT values increased in 35 eyes, de- creased in two eyes, and remained the same in two eyes. In the control group, it increased in 17 eyes, decreased in 10 eyes, and remained the same in nine eyes. The average first and last FBUT were 8.6 and 14.09 seconds, respectively, in the therapy group and

6.5 and 6.7 mm in the control group. The FBUT average increase rate was 5.318 (± 6.231 standard error) in the therapy group and

−0.5 (± 4.558 standard error) in control patients. Considering these

FIG. 1. A: Type 1: Regular, frequent branching ferning without spaces between leaves. B: Type 2: Smaller ferning pattern showing less branching and existing space between leaves. C: Type 3: Smaller leaves, little or almost no branching. Broad spaces attract attention. D: Type 4: Very loose or no crystallization. Mucus accumulation and amorphic structure attracts attention.

TABLE 1. Schirmer, fluorescein break-up time, and mucous fern test

DISCUSSION

Patient

Schirmer/F (mm)

Schirmer L (mm)

FBUT/F

(s)

FBUT/L

(s)

Fern/F grade

Fern/L grade

NAC is an effective mucolytic agent for chronic bronchitis therapy and pulmonary diseases that results in viscose mucus. It is

1 1 2 8 8 3 1

1 2 8 6 3 1

2 20 40 20 25 3 2

20 40 20 25 3 2

3 9 10 12 20 2 1

20 25 16 20 2 1

4 16 40 14 20 3 1

16 32 16 24 3 1

5 10 18 8 1 2 1

12 13 10 28 2 2

also used for preventing paracetamol toxicity and cardiac toxicity existing with doxorubicin. In addition, it is effective in preventing hemorrhagic cystitis existing with oxaphospharine. After 200 to 400 mg oral medication, it reaches the plasma concentration peak of 0.35to 4 mg/L in 1 to 2 hours. It may affect the active coal absorption; however, the reaction with other drugs and food has not been completely determined. It is not known yet whether NAC passes through the blood-brain barrier, placenta, or milk. Renal clearance is determined as 0.190 to 0.211 liter per hour per kilo- gram. After oral medication, half-life is 6.25 hours. There is very little information about NAC metabolism. The only defined prod- uct is inorganic phosphate. Most frequently nausea, vomiting, and diarrhea are reported as side effects. Biochemical and hematologic side effects have been observed but not proven clinically.7 It ap-

1 1

Schirmer/F Schirmer/L FBUT/F FBUT/L Fern/F Fern/L Patient (mm) (mm) (s) (s) grade grade

rates, there was a significant difference between the groups (p <

35 30 14 16 2 2

10 35 17 3 11 2 2

0.0001) (Figure 3). 11

According to the mucous fern test results, although in the

35 40 5 5 2 2

1 4 5 3 3 3

1 6 5 2 3 3

therapy group there was an improvement in ferning in 41 eyes

12 12 12 3 4 3 2

(95.4%), only 24 eyes improved in the control group (66%). The 13

average first and last fern grades were 2.9 and 1.62, respectively,

25 11 3 4 3 2

15 19 2 4 3 2

15 19 12 14 3 2

in the therapy group and 2.77 and 2, respectively, in the control group. The average increase rate was 1.2 (± 0.67 standard error) for the therapy group and 0.642 (± 0.63 standard error) for the control group. The difference between them was statistically sig- nificant (t 2.718, p 0.0096) (Tables 3 and 4).

Six eyes in the therapy group and eight eyes in the control group were found to show dryness during the study. In one patient, oral NAC was discontinued because of diarrhea. Other side effects of the drug included minor nausea in one patient and minor nasal leak in another; however, these patients did not discontinue using the drug.

14 6 1 5 3 2 2

4 1 4 4 2 2

15 8 3 2 2 4 4

F, first; L, last.

FIG. 2. Series 1: Therapy Group. Series 2: Control Group. Comparison of Schirmer-1 values between therapy and control groups.

not sufficient to explain these results by only observing mucolytic activity. Studies of the biochemical effect of NAC showed that it acts as a glutathione precursor.8 In a study with human umbilical endothelial cells, glutathione-deficient endothelial cell culture me- dium was prepared by exposing it to nonsulfur amino acids, and NAC was administered in doses to demonstrate existing glutathi- one synthesis.9 Again in a study with rabbit endothelial cells, butionin sulfoximine (BSO), which is a glutathione synthesis in- hibitor, reduced activity of NAC and as a result, NAC was ob- served to prevent endothelial damage in two ways: as a glutathione precursor and with antioxidant effects on nonperoxide radicals.10 Doxorubicin causes cardiac toxicity with peroxidative effect. It was demonstrated that NAC prevents lipid peroxidation, which was increased by doxorubicin.11 Oxidant fatty acid metabolism research in rat liver epithelial cells has shown that last product of free fatty acid metabolism increases the intracellular peroxide pro- duction, which was proven to be prevented by NAC pretreat- ment.12 Moreover, NAC has reduced the vascular damage in pa- tients with type II diabetes13 and has improved the liver microcir- culation in liver transplanted rats. In addition, there was a smaller

FIG. 3. Series 1: Therapy Group. Series 2: Control Group. Compari- son of FBUT between therapy and control groups.

increase in transaminases, and improvement in synthesis function was observed.14

We think that NAC will increase the FBUT by reducing evapo- ration and restoring eye tear quality. Shine and McCulley com- pared meibomian gland lipids of healthy and chronic blepharitis patients. Lipids were separated with a thin layer of chromolithog- raphy and marked out with gas chromolithography and mass spec- trograph. The patients who had dry eyes owing to evaporation without tear deficiency were detected to have lipid anomaly. It was thought that two phospholipids (phosphatidyl ethanolamine and sphingomyelin) have an effective role in the polarity of the lipid layer of tear sinema. Deficiency of these lipids increases evaporation owing to insufficient construction in polar phase, and eye dryness occurs owing to the evaporation.15 Increased evaporation of chronic blepharitis is also reported by other authors.16,17 Some of the authors inspected the meibomian gland triglyceride fat acids structure in patients in relation to meibomian keratoconjuncti- vitis and we submit defectively high saturated 30-carbon fatty acids.18–22 It was determined in another study that alpha oxida- tion activity in patients with chronic blepharitis was higher than olağan, and meibomian lipid changes may be related to peroxi- somal or endoplasmic reticulum irregularity.23 No increase has been recorded in the lysosomal activity of eye tears in chronic blepharitis.24–26

All these findings demonstrate that changes in the lipid content in chronic blepharitis play a major role in the pathogenesis and the continuation of the disease. Increase in lipase activity of colonized

TABLE 3. Tear function tests, increase in rates and statistical results in therapy and control groups

* p < 0.05, significant.

TABLE 4. Tear function tests average results in therapy and control groups

Staphylococcus or lipid destruction in olağan flora causes the de- struction of unsaturated fatty acids and stimulates lipid peroxida- tion. Oxidating substances like hydrogen peroxide increase the evaporation by impairing the tear sinema quality and shortening the break-up time of tear sinema by affecting viscosity and surface tension.19,27,28

In our study, patients using NAC showed a more significant improvement of tear sinema quality than patients having only local therapy. In our opinion, NAC not only acts as a mucolytic agent but also affects lipid metabolism. In dry eyes, NAC did not in- crease tear volume, but FBUT was significantly prolonged and mucous fern quality improved. It is possible that by preventing lipid peroxidation, NAC may provide continuity in the tear’s lipid layer, increasing surface tension force and prolonging tear break- up time. The mucous fern quality was significantly better in the therapy group than the control group. Mucous fern quality is a complex mechanism. At the beginning of the study, we expected that increased fluidity of the mucin would damage fern quality. Contrary to our expectations, fern quality improved, which may be related to the biochemical effects of NAC; however, our results are not conclusive.

In our study, we chose to use systemic administration of NAC for two reasons: it was too difficult to find a local preparation of the drug, and we wanted to observe the drug’s effect on the glands themselves. The NAC dosage used in our study (three times daily by 100 mg) was half the recommended single dose, avoiding un- necessary side effects.

The research done may be considered preliminary. New re- search examining lipid content, osmolarity, and lipase functional- ity (especially in the long term) is thought to be more of a guide than conclusive proof.

However, we still believe that NAC should be seen as a possible treatment for chronic blepharitis and for dry eyes.

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