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Diabetes Mellitus Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University

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1 Diabetes Mellitus Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University

2 Non-pharmacologic Therapy Diet – Medical nutrition therapy is recommended for all persons with DM Physical activity – Aerobic exercise – Goal: at least 150 minutes/week of moderate (50%–70% maximal heart rate) intensity exercise – Resistance training at least twice weekly 2

3 Benefits of Modest Weight Loss in Type 2 DM Loss of 20lb (10%) in obese subjects reduced FBG by 29mg/dL and A1C by 1.1% Loss of 10lb (5%) reduced DBP by 5% Loss of 6lb (3%) in obese men decreased – Total cholesterol by 17% – LDL-C by 9% – Triglycerides by 35% Arch Intern Med. 1987;147:1748 Diabet Med. 1990;7:228 Arch Intern Med. 1997;157:169 Metabolism. 1999;5:641

4 Medical Nutrition Therapy in Type 2 DM Management

5 Oral Medications

6 Mechanisms of Action of Oral DM Medications

7 Biguanide Generic Name Dose (mg)Recommended Starting Dosage (mg/day) Maximum Dose (mg/day) Duration of Action Metabolism or Therapeutic Notes Nonelderly Elderly Metformin500, 850, 1, mg twice a day Assess renal function 2,550Up to 24 hours No metabolism; renally secreted and excreted Metformin extended- release 500, 750, 1, –1,000 mg with evening meal Assess renal function 2,550Up to 24 hours Take with evening meal or may split dose; can consider trial if intolerant to immediate-release Suppression of basal hepatic glucose production Enhancement of peripheral (muscle) tissue insulin sensitivity – increases uptake of glucose in tissues No direct effect on β cells DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

8 Biguanide Most common adverse effects: GI – abdominal discomfort, stomach upset, diarrhea Weight loss can occur – anorexia – stomach fullness

9 Biguanide Contraindications High risk patients for lactic acidosis – CHF, hypoxic states, shock, septicemia, severe liver disease, alcohol use Renal insufficiency – SCr ≥ 1.4 mg/dL in women – SCr ≥ 1.5 mg/dL in men Intravenous dye procedures – risk of acute renal failure – withhold the day of procedure – may restart 2 to 3 days post-procedure

10 Biguanide Average HbA1c reduction: 1.5 to 2.0% FBG reduction: 60 to 80 mg/dL Reduce FBG levels when > 300 mg/dL Decrease plasma triglycerides & LDL-C by ~8 to 15% Increases HDL-C: 2%

11 Biguanide Weight loss: 2 to 3 kg Use in all type 2 DM patients – If tolerated & not contraindicated – Only oral antidiabetic agent proven to reduce mortality risk UKPDS shows metformin is best suited for obese type 2 DM patients; reduces mortality

12 Biguanide Summary Medication (A1C reduction) Mechanism of ActionComments Metformin (1.5% to 2%) Decreases hepatic glucose production Improves insulin sensitivity (Increases peripheral glucose uptake and utilization) Decreases intestinal absorption of glucose Modest weight loss is common Contraindicated in patients with renal impairment (CrCl < 60 mL/min) Gastrointestinal side effects are most common Low risk of hypoglycemia

13 Case 2: Medication-Induced Hypoglycemia TY is a 44 y/o male with Type 2 DM. This is his first visit with you. He is only taking Metformin 1000mg twice daily. Last week he was exercising and halfway through, he stopped because he was feeling extremely weak and was sweating profusely. He took his blood glucose and it was 68. He wants to know if this is a common symptom because of his medication.

14 Sulfonylureas Enhance insulin secretion – bind SUR receptors on pancreatic β cells – results in suppressed hepatic glucose production Classification: 1 st & 2 nd generation – differences in potency, adverse effects – no therapeutic superiority among agents Glyburide – requires adjustment for renal dysfunction; higher risk of hypoglycemia

15 Sulfonylureas Insulin Effect B L D HS B Type 2 DM Sulfonylurea

16 Sulfonylureas Generic NameDose (mg) Recommended Starting Dosage (mg/day) Equivalent Therapeutic Dose (mg) Maximum Dose (mg/day) Duration of Action Metabolism or Therapeutic Notes NonelderlyElderly 1st Generation Acetohexamide250, – ,500Up to 16 hours Metabolized in liver; metabolite potency equal to parent compound; renally eliminated Chlorpropamide100, Up to 72 hours Metabolized in liver; also excreted unchanged renally Tolazamide100, 250, – ,000Up to 24 hours Metabolized in liver; metabolite less active than parent compound; renally eliminated Tolbutamide250, 5001,000–2,000500– 1,000 1,0003,000Up to 12 hours Metabolized in liver to inactive metabolites that are renally excreted DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

17 Sulfonylureas Generic NameDose (mg) Recommended Starting Dosage (mg/day) Equivalent Therapeutic Dose (mg) Maximum Dose (mg/day) Duration of Action Metabolism or Therapeutic Notes NonelderlyElderly 2nd Generation Glipizide5, –5540Up to 20 hours Metabolized in liver to inactive metabolites Glipizide2.5, 5, 10, – hoursSlow-release form; do not cut tablet Glyburide1.25, 2.5, –2.5520Up to 24 hours Metabolized in liver; elimination ½ renal, ½ feces Glyburide, micronized 1.5, 3, 631.5–3312Up to 24 hours Equal control, but better absorption from micronized preparation Glimepiride1, 2, 41–20.5–12824 hoursMetabolized in liver to inactive metabolites DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

18 Sulfonylureas Most common side effect: hypoglycemia – Higher with chlorpropamide & glyburide – High risk patients require lower doses elderly renal/hepatic disease patients that skip meals vigorous exercise substantial weight loss Weight gain also common (~3kg) Less common adverse effects: rash, GI upset

19 Sulfonylureas Titrate sulfonylureas doses every 1 to 2 weeks Maximal effective dose ~60 to 75% stated max dose At equipotent doses, all sulfonylureas equally effective at lowering blood glucose

20 Sulfonylureas Average HbA1c reduction: 1.5 to 2% FBG reduction: 60 to 70 mg/dL Most patients do not reach glycemic goal with monotherapy – 1˚ failure: < 30 mg/dL drop in FBG low C-peptide high (> 250 mg/dL) FBG – 2˚failure: good initial response, but insufficient to reach or maintain glycemic goal 5 to 7% per year failure rate

21 Sulfonylureas Summary Medication (A1C reduction) Mechanism of ActionComments Glyburide; Glibenclamide Glipizide Glimepiride Gliclazide (1.5% to 2%) Stimulates insulin release from the β-cells of the pancreas May cause weight gain High propensity for hypoglycemic episodes

22 Meglitinides Generic Name Dose (mg) Recommended Starting Dosage (mg/day) Maximum Dose (mg/day) Duration of Action Metabolism or Therapeutic Notes NonelderlyElderly Nateglinide60, with meals 120 mg three times a day Up to 4 hours Metabolized by cytochrome P450 (CYP450), CYP2C9, and CYP3A4 to weakly active metabolites; renally eliminated Repaglinide0.5, 1, 20.5–1 with meals 16Up to 4 hours Metabolized by CYP3A4 to inactive metabolites; excreted in bile Stimulate insulin secretion from pancreatic β cells – require presence of glucose Similar mechanism to sulfonylureas – faster onset, shorter duration DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

23 Meglitinides Insulin Effect B L D HS B Type 2 DM Meglitinide

24 Meglitinides Most common adverse effect: hypoglycemia – less than with sulfonylureas Weight gain may occur – repaglinide: 2 to 3 kg – nateglinide: < 1 kg CYP3A4 inducers or inhibitors may interact with repaglinide May use in patients with renal insufficiency Use with caution in severe hepatic impairment

25 Meglitinides May be used as monotherapy or in combination with metformin or TZDs in Type 2 DM Dose up to 30 min prior to each meal – dose can be skipped if a meal is skipped – meals low in carbohydrates may not need a dose Average HbA1c reduction < 1% – Reduces FBG by ~60mg/dL Useful in reducing postprandial glucose excursions in patients close to glycemic goals Patients having a poor response to sulfonylurea therapy are not likely to respond if these drugs are added

26 Repaglinide vs. Nateglinide Monotherapy Diabetes Care 2004;27:

27 Meglitinides Summary Medication (A1C reduction) Mechanism of ActionComments Repaglinide Nateglinide (0.5% to 1%) Stimulates the release of insulin from the β- cells of the pancreas Shorter acting than the SUs Taken with meals The dose should be skipped if the meal is skipped Lower risk of hypoglycemia than with SUs May cause weight gain

28 α-Glucosidase Inhibitors Competitively inhibit enzymes in the small intestine – delay sucrose & complex carbohydrate breakdown Absorption of glucose is delayed to the distal portion of the small intestine resulting in a reduction of “ peak ” postprandial blood glucose concentrations Reduce postprandial hyperglycemia DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: Generic Name Dose (mg)Recommended Starting Dosage (mg/day) Maximum Dose (mg/day) Duration of Action Metabolism or Therapeutic Notes Nonelderly Elderly Acarbose25, 50, mg one to three times a day 25–100 mg three times a day 1–3 hoursEliminated in bile Miglitol25, 50, mg one to three times a day 25–100 mg three times a day 1–3 hoursEliminated renally 28

29 Without Pharmacotherapy α-Glucosidase Inhibitors With Pharmacotherapy

30 α-Glucosidase Inhibitors

31 Adverse effect: – GI side effects most common flatulence, bloating, abdominal discomfort, diarrhea – May elevate serum aminotransferase Contraindications: – IBD – colonic ulceration – intestinal obstruction – cirrhosis 31

32 α-Glucosidase Inhibitors Efficacy – Reduce postprandial glucose 40 to 50 mg/dL – FBG relatively unchanged (~10% reduction) – Average HbA1c reduction: 0.3 to 1% – Beneficial in patients close to target HbA1c with near-normal FBG but high postprandial levels – Do not affect the absorption of simple sugars such as glucose and lactose 32

33 α-Glucosidase Inhibitor May be monotherapy or used with metformin, sulfonylureas, insulin Initiate with very low dose – 25 mg with one meal a day Increase gradually to maximum dose – 50 mg TID patients ≤ 60 kg – 100 mg TID patients > 60 kg Take with 1 st bite of a meal 33

34 Alpha-glucosidase Inhibitors Medication (A1C reduction) Mechanism of ActionComments Acarbose Miglitol (0.3% to 1%) Delays the breakdown of complex carbohydrates into glucose The absorption of glucose is delayed in the distal portion of the small intestine Can cause flatulence, abdominal pain, diarrhea Not as effective as the other oral agents Considered 2 nd or 3 rd line therapy

35 TZDs: Thiazolidinediones May be used in type 2 DM therapy Enhance insulin sensitivity at muscle, liver, fat tissues Decrease hepatic glucose production Requires presence of insulin DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: Generic Name Dose (mg)Recommended Starting Dosage (mg/day) Maximum Dose (mg/day) Duration of Action Metabolism or Therapeutic Notes Nonelderly Elderly Pioglitazone15, 30, hoursMetabolized by CYP2C8 and CYP3A4; two metabolites have longer half-lives than parent compound Rosiglitazone2, 4, 82–428 mg/day or 4 mg twice a day 24 hoursMetabolized by CYP2C8 and CYP2C9 to inactive metabolites that are renally excreted 35

36 Thiazolidinediones Usual reduction in HbA1c of 1.5% - 2.5% Decreases in blood glucose can be seen within 2-4 weeks Maximum glucose lowering effects may take up to 12 weeks Demonstrated perseverance of effect for up to 1-2 years

37 TZD Adverse Effects May increase ALT – CI if ALT > 2.5 times upper limit of normal (ULN) – Discontinue if ALT > 3 times ULN – Troglitazone (1 st approved TZD) removed from market in 2000 due to deaths from liver failure Fluid retention – Edema, dilutional anemia, pulmonary edema, HF – CI in NYHA Class III & IV – Black box warning for heart failure 37

38 TZD Adverse Effects Weight Gain – 1.5 to 6 kg – Fluid retention & fat accumulation Increased fracture risk – upper & lower limbs of postmenopausal women Ovulation – aovulatory patients can resume ovulation – pregnancy & contraception precautions required – pregnancy category C 38

39 TZDs Average HbA1c reduction ~1.5% FBG reduction: 60 to 70 mg/dL at max doses Maximal glycemic-lowering effects after 3 to 4 months Triglycerides: – pioglitazone: 10 to 20% decrease – rosiglitazone: neutral effect LDL: – pioglitazone: no significant increase – rosiglitazone: 5 to 15% increase HDL: both increase 3 to 9 mg/dL 39

40 Thiazolidinediones Summary Medication (A1C reduction) Mechanism of ActionComments Rosiglitazone Pioglitazone (1.5% to 2.5%) Improves insulin sensitivity in skeletal muscle and adipose tissue Decreases hepatic glucose output FDA-imposed restricted use of rosiglitazone due to cardiovascular ischemic risk Risk of bladder cancer with pioglitazone Long onset and prolonged effects after discontinuation Can cause weight gain, edema, and worsen CHF

41 “Incretin Effect” Normal Weight: Non-Diabetic Subjects Normal Weight: Diabetic Subjects Plasma Insulin Responses to Oral and Intravenous Glucose Oral Glucose Intravenous Glucose Non-Diabetic Subjects (glucose range mmol/L) Diabetic Subjects (glucose range mmol/L) Oral Glucose Intravenous Glucose Data from: Perley M, et al. J Clin Invest 1967; 46: Plasma Insulin (  U/mL) Plasma Insulin (  U/mL) Time (min)

42 Incretins Peptide hormones secreted by enteroendocrine cells in the GI tract Modulate pancreatic islet secretions Other effects on nutrient homeostasis Two major incretins that affect glucose metabolism –GLP-1: glucagon-like peptide-1 –GIP: glucose-dependent insulinotropic polypeptide

43 GLP-1 Produced by intestinal L-cells, which are located predominately in the ileum and colon (distal portion of the gut) Potent insulinotropic hormone Plasma levels increase rapidly in response to meals (carbohydrate & lipid) Once secreted it is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV) t 1/2 ~ 2 min Type 2 DM & Impaired Glucose Tolerance (IGT) present with lower plasma GLP-1 compared to healthy controls

44 GLP-1 Secretion and Metabolism Mixed Meal Intestinal GLP-1 Release Plasma GLP-1 (7-36) Active DPP-IV GLP-1(9-36) Inactive GLP-1 Actions Rapid Inactivation (>80% of pool) Renal Clearance DPP-IV = Dipeptidyl peptidase-IV Deacon CF, et al. Diabetes. 1995;44:

45 GLP-1 Modes of Action in Humans GLP-1 is secreted from the L-cells in the intestine This in turn… Stimulates glucose- dependent insulin secretion Suppresses glucagon secretion Slows gastric emptying Long term effects demonstrated in animals… Increases beta-cell mass and maintains beta-cell efficiency Reduces food intake Upon ingestion of food… Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:

46 Strategies to Enhance Incretin Action in Diabetes Glucagon-like peptide-1 (GLP-1) analogues* Exenatide (synthetic Exendin-4)* Dipeptidyl peptidase-IV (DPP-IV) inhibitors * Incretin mimetic agents

47 DPP-IV Inhibitors Mixed Meal Intestinal GLP-1 Release Plasma GLP-1 (7-36) Active DPP-IV GLP-1(9-36) Inactive GLP-1 Actions Rapid Inactivation (>80% of pool) Renal Clearance DPP-IV = Dipeptidyl peptidase-IV Deacon CF, et al. Diabetes. 1995;44: ↑ Activity Incretin Enhancement

48 DPP-IV Inhibitors Inhibit DPP-IV which degrades GLP-1 – prolongs GLP-1 t½ – GLP-1 deficient in type 2 DM Partially reduces elevated postprandial glucagon Stimulates glucose-dependent insulin secretion 48

49 DPP-IV Inhibitors May be used as monotherapy or in combination therapy Average HbA1c reduction 0.7 to 1.0% Mild hypoglycemia may occur Postmarking reports of serious hypersensitivity reactions – anaphylaxis – angioedema – exfoliative skin conditions (Stevens-Johnson syndrome) 49

50 Dipeptidyl peptidase-4 (DPP-4) Inhibitors Summary Medication (A1C reduction) Mechanism of ActionComments Linagliptin Saxagliptin Sitagliptin Vildagliptin (0.7% to 1%) Inhibits the degradation of endogenous incretins which increases insulin secretion Decreases glucagon secretion Weight neutral Rare instances of hypoglycemia Considered 2 nd line therapy Reports of acute pancreatitis

51 Non-insulin Injectable Medications

52 Time After Meal (h) Plasma Exendin-4 Concentration (pg/mL) Exendin-4 in the Gila Monster Exendin-4 was originally isolated from the salivary secretions of the Gila monster Exendin-4 was subsequently found to circulate as a meal-related peptide in this animal Exendin-4 has possible endocrine function in the lizard Heloderma suspectum (Gila monster) Data from: Young AA. Glucagon-like peptide-1, exendin and insulin sensitivity. In Hansen B, Shafrir E, Editors. Insulin Resistance and Insulin Resistance Syndrome. 1st ed. Harwood Academic Press; 2002, mice 1 rat

53 Exenatide: Clinical Pharmacology Adverse Effects: Nausea Jittery Dyspepsia Vomiting Dizziness Hypoglycemia (with sulfyl use) Diarrhea Headache Weight Loss Dosage: 5 μg BID within a 60-minute period before the morning and evening meals Based on clinical response dosage may be increased to 10 μg BID after 1 month of therapy Storage: Exenatide should be refrigerated (at all times) at 36 º F to 46 º F, protected from light Pen should be discarded 30 days after first use, even if some drug remains in the pen

54 Exenatide Average HbA1c reduction ~0.9% Significantly decreases postprandial glucose excursions Modest effects on FBG Average weight loss in studies: 1 to 2 kg over 30 weeks – long-term, open-labeled trials show continued weight loss for at least 2.5 years with 10 mcg BID dose Improvements in triglycerides & HDL seen with exenatide 10 mcg BID 54

55 Nausea Is Dose-dependent and Decreases Over Time Buse JB, et al. Diabetes Care. 2004;27: >4-8>8-12>12-16>16-20>20-24>24-28>28 Treatment (wk) Incidence of Nausea (% ITT Subjects) 10 µg 5 µg Placebo

56 Effect of Exenatide on Body Weight Buse JB, et al. Diabetes Care. 2004;27:

57 Once-daily injection of Liraglutide covers 24-h BG profile in type 2 diabetes Adapted from: Degn et al. Diabetes 2004;53: h glucose AUC (mmol/l/h, mean ± SE) ± ± 14.0 (p = 0.01) Plasma glucose (mmol/l) Injection (08.00) Time after injection (hours) Placebo Liraglutide (6 µg/kg OD) n=13

58 Liraglutide Effect on FBG and Weight Fasting serum glucose Weight change mM % p< p<0.015 Key observations: Observations from liraglutide and metformin versus metformin and a sulfonylurea Effect observed in the absence of hypoglycaemia 1mM = 20 mg/dL Liraglutide and metformin Glimepiride and metformin

59 Liraglutide: Effect on Weight Note: Data from the double-blind, double-dummy, randomised, parallel group dose titration phase 2 study including a total of 144 patients with an average HbA1c of %. All changes are from baseline; that is, FSG of mM and an average weight of kg. Glimepiride and metformin Mean change in body weight from baseline (%) Time (weeks) Continuing weight loss Liraglutide and metformin

60 Summary A 24-hour pharmacodynamic profile – Once-daily injection due to 12 hr half-life Multiple anti-diabetic actions – Increases insulin and lowers glucagon secretion – Rapid and sustained glycaemic effect – Weight control –  -cell mass increased in animal models –  -cell function improved in type 2 diabetes Strictly glucose-dependent actions – Very low hypoglycemia risk (no major and few minor events) – Counter-regulatory response to hypoglycaemia not impaired Well-tolerated – Mild, transient GI-symptoms; no antibodies (12-week data)

61 Glucagon-like, peptide-1 (GLP-1) Mimetic Medication (A1C reduction) Mechanism of ActionComments Exenatide Exenatide weekly Liraglutide (1% to 1.5%) Stimulates GLP-1 receptors which increases production of insulin in response to high blood glucose levels Inhibits post-prandial glucagon release Slows gastric emptying Injections Promotes weight loss Nausea and diarrhea are common Induces satiety

62 Pramlintide Adjunctive therapy for patients using insulin Synthetic analog of amylin – neurohormone co-secreted from β-cells with insulin Suppresses postprandial glucagon secretion Reduces food intake Slows gastric emptying 62

63 Pramlintide Subcutaneous injection in abdomen or thigh – variable absorption with arm injection Adverse effects: – GI most common – nausea, vomiting, anorexia – may decrease over time – dose-related, slowly titrate dose upwards May delay absorption of other medications; slow gastric emptying 63

64 Pramlintide Reduce preprandial insulin dose 30 to 50% at pramlintide initiation Basal insulin dose may be reduced if FBG close to goal Dosing – Type 2: 60 to 120 mcg prior to meals – Type 1: 15 to 60 mcg prior to meals 2.5 units on 100 units/ml insulin syringe = 15 mcg of pramlinitide 64

65 Pramlintide Average HbA1c reduction 0.4 to 0.6% Decreases prandial glucose excursions Little effect of FBG concentrations Main advantage in type 1 DM is that it stabilizes wide postprandial glycemic swings Average weight loss in controlled trials: 1 to 2 kg 65

66 Warnings and Precautions

67 Case 3: Non-Insulin Injectables YO is a 52 y/o female with Type 2 DM and central obesity. She was recently started on liraglutide and is now taking 1.8mg daily. She is nauseous after eating and states that this occurs even with her favorite #1 and #3 meal combos from McDonalds. She states that she knows that her diet is not good. How do you respond?

68 Treatment Algorithm 3 rd Agent 2 nd Agent 1 st Agent MetforminSU TZD or DDP-4 or GLP-1 or insulin TZD SU or DPP-4 or GLP-1 or insulin DPP-4 inhibitor SU or TZD or insulin GLP-1 agonist SU or TZD or insulin Insulin (usu. Basal) TZD or DPP-4 or GLP-1

69 Drug Combination Change in HbA 1c (%) Number of Studies Number of Subjects Sulfonylurea + metformin– Sulfonylurea + insulin– Meglitinide + thiazolidinedione– Metformin + insulin– Sulfonylurea + α-glucosidase inhibitor– Metformin + meglitinide– Insulin + α-glucosidase inhibitor– Insulin + thiazolidinedione– Sulfonylurea + thiazolidinedione–1.1121,315 Metformin + exenatide–0.821,070 Metformin + vildagliptin– Metformin + thiazolidinedione– Metformin + α-glucosidase inhibitor– Add-On a Dual Therapy: Average HbA1c Reduction a Reductions are averages and do not imply superiority or inferiority of a combination. 69

70 Medication-specific Therapy High HbA1C, High FBGHigh HbA1C, Goal FBG, High PPBG FASTING/BASALPOST-PRANDIAL Metformin TZDs Sulfonylureas NPH Insulin Long-acting insulins Liraglutide Glinides Α-glucosidase inhibitors Colesevelam DPP-4 inhibitors Incretin mimetics (exenatide > liraglutide) Fast/rapid acting insulins Pramlintide

71 Diabetes Mellitus Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University


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