A Thesis paper submitted to the Department of Pharmacy,

East West University in conformity with the requirements for

the Degree of Bachelor of Pharmacy.

A collaborative study between Department of Pharmacy,

East West University and Skin Department, Bangladesh

Institute of Research and Rehabilitation in Diabetes,

Endocrine and Metabolic Disorders.

Steroid, pharmacologically very important & useful that is essential and can be used for different

indications & treatment of diseases.

Steroid has different complications like folliculitis, steroid rosacea, perioral dermatitis, skin atrophy,

delayed wound healing, striae, purpura, depigmentation, acneiform eruptions, allergic contact

dermatitis, hyperglycemia, growth reterdation, cataract, Cushing’s syndrome, glaucoma etc. For

these reasons, use of steroids should be very metticulous & rational to avoid those side effects

and complications.

Depending on substitution, subtraction, addition and replacement, pharmacologically steroid has

been classified into two groups: a) mineralocorticoids (Aldosterone, Desoxycorticosterone,

Corticosterone, Cortisol, Cortisone & 9-alpha fluorocortisol) and b) glucocorticoids

(Corticosterone, Cortisol, Cortisone, Prednisone, Methylprednisone & Dexamethasone).

In dermatology prednisolone and triamcinolone acetonide are indicated in different skin diseases,

drugs can be used in the same indications like Urticaria, Leprosy, Lichen Planus, sweet

syndrome, Seborrheic Dermatitis, Pompholyx, Prurigo Nodularis, Pemphigus vulgaris, Hand

Eczema, Bullous, Vasculitis etc.

Our purpose of this study is to see the variation of side effects of prednisolone and triamcinolone

acetonide in the skin diseases where both the steroids are indicated.

Study subjects were divided into two groups: group1 (prednisolone) and group2 (triamcinoloneacetonide). Single dose of triamcinolone acetonide was given to 15 patients and differentamount of dose of prednisolone was given to 15 patients. Their glycemic status was measuredbefore steroid (baseline) at 0 week which was compared with the blood sugar during period ofweek1, week2 and week3 after steroid.

Blood glucose level (fasting & 2h ABF) in both groups (prednisolone and triamcinolone acetonide)rose significantly after week1, week2 & week3.

The study showed, triamcinolone acetonide had little tendency to increase blood glucose level whencompared with prednisolone. Fasting blood glucose ≥ 10 mmol/l was considered as an arbitraryline for control of blood glucose. Triamcinolone acetonide did not cross arbitrary line 10 mmol/lbut prednisolone crossed the arbitrary line. Thus control of blood glucose level remained staticin triamcinolone. However blood glucose in prednisolone might remain uncontrolled. Bothgroups showed significant improvement of skin diseases.

Thus triamcinolone acetonide is the better choice in the treatment of skin diseases with diabetesmellitus.

Diabetes is a disease in which the body does not produce or properly use insulin. It has high bloodsugar levels which if not well-controlled can lead to long-term complications affecting variousorgans in the body such as the eye, kidney, nervous system, skin and blood vessels. Skinproblems are very common in diabetics and it is a common condition which frequently has skinmanifestations. The attachment of glucose to protein may result in a profound effect onstructure and function of that protein, and account for clinical manifestations of the disease. Ithas been suggested that increased cross linking of collagen in diabetic patients is responsiblefor the fact that their skin is generally thicker than that of non-diabetics. Advanced glycosylationend products are probably responsible for yellowing of skin and nails. Increased viscosity ofblood due to stiff red blood cell membranes results in engorgement of the post-capillary venulesin the papillary dermis, detected as erythema of the face, or periungual erythema. It issuggested that these skin changes may eventually be used as a reflection of the patient'scurrent as well as past metabolic status (DermAtlas). Diabetic skin conditions include abnormalgrowths, ulcers, infections and changes in the skin itself (National skin centre). There are manyreasons people with diabetes face increased risk of skin problems:

Impaired circulation

Hyperglycemia (high glucose)

Hyperlipemia (high levels of fats in the blood)

Suppressed immune system

Diabetic neuropathy (nerve damage)

High blood pressure

The key to prevention of many types of diabetic skin conditions is regular good hygiene and controlof risk factors. Treatments depend on the particular disorder but often include surgical incisionor debridement (removal of damaged tissue) and antibiotics, antifungals or other medications(National skin centre). Some common skin diseases associated with Diabetes Mellitus areUrticaria, Leprosy, Lichen Planus, sweet syndrome, Seborrheic Dermatitis, Pompholyx, PrurigoNodularis, Pemphigus vulgaris, Hand Eczema, Bullous, Vasculitis etc. (ANDREWS’). Shortlyafter the synthesis of hydrocortisone in 1951, topical glucocorticoids and mineralocorticoidswere recognized as effective agents for the treatment of skin diseases. It is also used to treatmany inflammatory skin diseases. Maibach and Stonghton, 1973 have divided 20dermatological disorders that are very responsive and those that require concentrations ofsteroids, occlusion or intralesional administration. Various side effects of these preparations arealso associated with its different uses. So attention must be paid to the concentration of steroidused. In clinical trial found that glucocorticoids increase blood glucose level and causehyperglycemia. As a result physicians do not use corticosteroids due to the metabolicdeterioration of blood glucose level with diabetes. Glucocorticoids work on carbohydrate, lipid,and protein and produce glucose. As a result hyperglycemic episode occur (Goodman, Gilman).If our diabetes is well controlled, many of these skin problems can be averted. This requirescompliance with a diabetic diet, medication and regular check-ups with our doctor. When thereare serious complications such as bacterial skin infections, gangrene, seek immediate medicalattention. Consult doctor early. We may need hospitalization. If left untreated, thesecomplications may lead life-threatening. Infected ulcers and skin infections need to be treatedwith antibiotics, antifungals and glucocorticoids (prednisolone and triamcinolone acetonide)(Reza B Zaid, 1996). Now, most commonly used drugs are corticosteroids, especiallyglucocorticoids (prednisolone and triamcinolone acetonide) and others as a combinationtherapy. The aim of this controlled study was to determine the efficacy of steroids in treatingdiabetic with different dermatoses as well as to see the effects on glucose metabolism.

A randomized, parallel- group study was conducted from March 2008 through December 2008 at the

Bangladesh Institute of Research and Rehabilitation for Diabetes, Skin Department (BIRDEM),

Shahbagh, Dhaka, Bangladesh.

Patients

In the study, 30 patients (both male and female) with NIDDM (cases) were taken between 30-70

years as healthy volunteers. They were selective and subdivided grouped as 1) group1;

prednisolone (15 patients), the standard drug and 2) group2 (15 patients), the study,

triamcinolone acetonide. Blood sugar levels were estimated for different skin diseases

(Urticaria, Leprosy, Lichen Planus, sweet syndrome, Seborrheic Dermatitis, Pompholyx, Prurigo

Nodularis, Pemphigus vulgaris, Hand Eczema, Bullous, Vasculitis etc.) where steroid was

indicated in every weekly for four weeks. Pregnant, nursing women were excluded from the

study. Patients with other clinical complication other than type2 diabetes and skin diseases

were excluded from the study. Their state of blood pressure, weight was recorded before

starting of steroid therapy. Their glycemic status as well as individual’s diet and exercise habit

were recorded at the base line and every week for four weeks. To avoid other factors that are

responsible for raising individual’s blood sugar all the patients were instructed to continue the

same diet and exercise habit as they were in basal state.

Statistical Analysis:

Data were analyzed by manually. All the data of the study sample was entered from each patient’s

history sheet and data of standard sample was entered from all enquiry sheets. Descriptive

statistics were done for major variables of interest, including the population, age distribution,

drug for skin diseases, drug for diabetes and different concentration of blood sugar levels using

Student’s t-test. A probability level of 0.05 was considered statistically significant.

Total dose of steroid incase of triamcinolone acetonide group is 69.32 mg/ml, of which 34.66 mg/ml

was given IM on “0 week” and 34.66 mg/ml was given at the beginning of 3rd week. Patients

with triamcinolone acetonide had blood sugar before steroid was 7.6 mg/dl and 9.9 mg/dl at 1st

week, 9.82 mg/dl at 2nd week and 9.05 mg/dl at 3rd week after giving steroid. Though patients

were taken steroid, their blood glucose levels still remain controlled (shown in Fig1). Most of

skin diseases were well controlled and cured by triamcinolone acetonide. Antidiabetic drugs

were no needed to change during treatment.

Total dose of oral prednisolone group is 44.4 mg, of which 18.3 mg was given at 0

week, 13 mg at 1st week, 7.8 mg 2nd week and 5.3 mg was given at 3rd week.

Patients with prednisolone had blood sugar before steroid was 8.5mg/dl. After giving

steroid blood sugar was 12.13mg/dl at 1st week, 11.54mg/dl at 2nd week and

11.37mg/dl at 3rd week. Here after administered prednisolone, blood glucose level

was not controlled (shown in Fig2) but most of the diseases were cured properly.

Antidiabetic drugs were changed during treatment.

Significance:

In the study, I considered 95% significance. After giving drugs bothprednisolone (15 patients) and triamcinolone acetonide (15 patients),blood sugar level raised significantly from 0 week to 1st week, 0 week to2nd week and 0 week to 3rd week in all patients. But prednisolone hastendency to increase blood sugar higher than that triamcinolone. Intriamcinolone acetonide patients’ blood sugar level rose from 2 to 3 mg/dlwhereas in prednisolone patients’ blood sugar level raised 5 to 15 mg/dlthan baseline or 0 week.

Drug type blood sugar level 0 week to 1st

week0 week to 2nd

week0 week to 3rd

week

Triamcinoloneacetonide

Fasting P<0.01 P<0.01 P<0.05

2h ABF P<0.01 P<0.01 P<0.05

Prednisolone Fasting P≤0.05 P<0.05 P<0.05

2h ABF P<0.05 P<0.05 P<0.05

Week

Patients Baseline 1st week 2nd week 3rd week

SerialNo.

Fasting 2hABF Fasting 2hABF Fasting 2hABF Fasting 2hABF

1 7.1 13 9 15.8 9 14.7 8.5 14.7

2 9.9 11.4 12.1 14.3 11.1 12.7 9.9 12.7

3 5.4 6.9 4.84 5.3 6.2 7.9 6 7.9

4 6 6.7 12 16 10 14.9 9.5 14.9

5 8.8 10 8.2 12 9 12.5 8.1 12.5

6 12.8 17.1 11.5 14.9 8.9 13.4 8 13.4

7 7.0 14.5 8.3 17 8 15.9 7.9 15.9

8 7.5 13 6.2 12.1 13.7 19.2 10 19.2

9 5.1 8.1 9.5 12.4 8.9 11.1 8.3 11.1

10 7.7 9.1 11.1 13 9.9 11.5 9.5 11.5

11 10.1 11.5 13.5 16 11.7 14.3 10.5 14.3

12 6.7 12 10.3 14.9 10 12.7 9.7 12.7

13 8.7 13.1 11.5 17.3 10.9 15.3 10 15.3

14 5.5 13.6 10.5 17.1 10.1 14.3 9.8 14.3

15 5.9 11.5 10 14 9.9 12.3 10 12.3

Mean 7.6 11.43 9.9 14.14 9.82 13.51 9.05 12.653

Week

Patients

Baseline 1st week 2nd week 3rd week

SerialNo.

Fasting

2hABF Fasting

2hABF Fasting

2hABF Fasting

2hABF

1 7.4 13.1 11.5 20.7 11 17 10.5 16.52 6.1 14.2 9.1 16.3 9.5 14.7 10 15.93 8 16.3 11.1 20.5 10.9 16 10.5 16.34 14.3 24.7 18.3 27.3 16.1 25 15 25.95 6.4 9.8 9 12.4 9.5 13.5 10 13.36 23.6 25.9 7.1 9.1 10.3 18.5 12.5 19.77 8.6 14,2 5.2 8.2 7.3 10 9.7 10.58 8.9 10.3 10.4 12.2 9.3 10.5 10 12.99 4.2 8 15.1 20.5 13.1 16.5 11.9 14.5310 5.4 13.2 14.9 23 12.5 16 11.5 14.8511 7.2 12.4 13.3 20.5 11.9 16 10.9 15.412 4.6 5.8 10.5 14.9 11 13.7 10.5 1213 6.9 11.1 11.3 20.1 10.7 15.5 10.3 13.514 7.8 9 19.1 22.5 16.3 17.5 14.7 14.715 8.1 9.9 16 20 13.7 16.1 12.5 11.5Mean 8.5 13.19 12.13 17.5 11.54 15.8 11.37 15.17

Graph below is showing, Fasting and 2h ABF in individual patient from week 0,

1, 2 and 3 in prednisolone and triamcinolone acetonide.

Patients of triamcinolone acetonide; when they were in the treatment of skin, dose of

antidiabetes drug would not change in most of patients. Dose modification was rare. Among

fifteen patients one patient who took insulin, his dose was modified (decreased the dose

unit) as his sugar level become controlled. On the other hand in prednisolone patients,

antidiabetes drug dose would not change in most of patients but one patient who took

insulin; their dose was adjusted by increasing or decreasing dose amount ( 2) to control

their blood sugar level. In both groups dose frequency was observed by Comparing drug

treatment from 0 week to 1st week, 0 week to 2nd week & 0 week to 3rd week. For patients

who took Prednisolone, dose adjustment is needed whereas in triamcinolone patients did not

need to increase dose to control sugar level .

Efficacy:

During the study, signs and symptoms improved in both treatment groups except 7 out of 30

patients.

Tolerability:

Complication due to drug with prednisolone and triamcinolone, was followed up. Clinical

follow up showed no complications such as peptic ulcer disease, myopathy, depression,

acne, nausea, hypertention, osteoporosis, adrenal insufficiency and stria. All diseases were

well tolerated by prednisolone and triamcinolone.

Corticosteroids have profound effects on carbohydrate metabolism: stimulating liver to form glucosefrom amino acids and glycerol [14]. In the periphery, corticoids decrease glucose utilization,increase protein breakdown and activate lipolysis, thereby providing amino acids and glycerolfor gluconeogenesis [14]. The net result is increased in blood glucose levels because of theseeffects on glucose metabolism, treatment with glucocorticoid can worsen control in patients withovert diabetes and can precipitate onset of hyperglycemia in patients who are predisposed [14].One case study showed that prednisolone 20 mg OD for two months followed by dose taperingto 10 mg OD as maintenance dose was given to a patient as an immunosuppressive agent andpatient got steroid induced diabetes mellitus [14, 20]. Our study also showed that prednisolone18.3 mg OD for one month followed by dose tapering to 5.3 mg OD was given to diabetespatients for the treatment of skin diseases and patients blood sugar levels increasedsignificantly after administration of oral prednisolone. However, effects of glucocorticoids onhyperglycemia usually remit within 48 hours of discontinuation of oral administration [14].

In the study of tapering off prednisolone after renal transplantation showed that reduction in dailyprednisolone dose leads to decline in blood glucose level [15]. Weight gain was associated withincreasing blood glucose level [15]. Each 1mg reduction of prednisolone dose leads to anestimated decline in 2h ABF of 0.12 mmol/l based on multiple linear regression model [15]. Wealso observed that tapering off prednisolone dose leads to decline in blood glucose level(fasting and 2h ABF).

The safety of steroids in diabetes has been a subject of debate.

Skin diseases are very much common with diabetes patients and those are treated by steroids.

Steroids are an effective treatment of different skin diseases in the subjects of diabetes [1]. In ourstudy both groups showed significant improvement of skin diseases. Symptoms andimprovement of skin diseases were observed by the physicians.

Steroids are used in the treatment of erosive lichen planus with diabetes is of considerable concernbecause steroids can antagonize the action of insulin, lead to hyperglycemia and need selfmonitoring during steroid therapy [23]. Triamcinolone acetonide treat oral lichen planuscompletely [28]. We observed that lichen planus was well treated by the apllication ofintramascular injection, triamcinolone acetonide.

Systemic corticosteroids are usually chosen first to treat patients with generalized forms of anyautoimmune bullous disease [26]. The efficacy of systemic steroids in patients is based on thestudy of patients with pemphigus vulgaris [26]. Before systemic steroids were available most ofthe patients with that condition died [26]. Prednisolone causes adverse effect after given highdose [26]. After given low dose patients were benefited [26]. Many early case reports showedthat steroids therapy is beneficial as it treat disease by blocking further injury or inhibited theinciting cell mediated immunologic reaction [26]. Bullous disease and pemphigus vulgaris werewell treated by the administration of oral prednisolone.

Leprosy is a disease caused by Mycobacterium leprae that initially affects the peripheral nervoussystem with patients exhibiting contrasting clinical, immunological pathological manifestationand well treated by steroids (prednisolone) [31]. During treatment period we observed thatreactive leprosy was improved after giving prednisolone.

Paravertebral lumbosacral injection of triamcinolone acetonide resulted in statistically significant

decrease in pruritis, burning, tingling, and pain and improved quality of life [34]. This is also true for our

study.

Our study limitation was that we have done our study by taking small number of patients. As a result

further large study is necessary to confirm our findings.

Some general points were noticed during the study. They are:

•Diabetes patients who are in diet can be treated by steroids with weekly observation.

•Diabetes patients who are in oral hypoglycemics can be treated by steroids with careful observation,

twice per week.

•Diabetes patients who are in insulin need grate care and daily observation while treating by steroids.

•When increase the dose of steroids may need to modify dose of hypoglycemics either patients will

face hyperglycemia.

•When reduce the dose of steroids must reduce the dose of hypoglycemics either patients will face

hypoglycemic episode.

Effect of steroids on blood glucose level reduces with the improvement of skin diseases and when

patients are not in stress.