the SQUARE-Q V13 N 2 · 2018-02-20 · enous Thrombosis (DVT)" which is more commonly also itiligo", the condition can be cosmetically disfiguring andaffects 0.1-2% of the world's

APRIL 2005 VOL 13 NO 2 ISSN 1681-5552

Published as a service to medical professionals by

h e a l t h c a r e b u l l e t i n

Polycystic Ovary SyndromeDeep Venous ThrombosisVitiligoChildhood AsthmaProduct Profile- Comet® & Comet XR®

SQUARE in International BusinessMedical Breakthrough

Get the

latest health news!

Get “e-SQUARE” online!

e-mail to us at

“[email protected]”

Dear Doctor:

We are very happy to present you the second issue of "the SQUARE" of 2005!

We express our heartiest appreciation for your momentous feedback regarding

the first issue of this year and also delighted to have many of you join our

online "e SQUARE" community!

In this issue we published a special feature on "Polycystic Ovary Syndrome

(PCOS)", one of the most common hormonal abnormalities in women of

reproductive age and is a leading cause of infertility. We also bring you all

the details on "Deep Venous Thrombosis (DVT)" which is more commonly

seen in adults over age 60 but can occur in any age group. We also

focused on "Vitiligo", the condition can be cosmetically disfiguring and

affects 0.1-2% of the world's population, irrespective of gender and

race. In addition, we emphasized on the essentials of "Childhood

Asthma", one of the most common chronic diseases of childhood and

a greater percentage of children suffer from this condition now than

ever before.

Besides, we have our regular feature on "Product profile", "Medical

Breakthrough" and, "SQUARE in International Business".

We believe you will enjoy reading this publication and that the

contents provided will prove helpful towards your goal of

optimum health!

Wishing all of you a safe, healthy and peaceful life.

From the Desk of Managing Editor

Managing EditorOmar Akramur RabMBBS, FCGP, FIAGP, FRSH

PG Dip. Business Management (India)

Executive EditorLatifa Nishat

MBBS

Associate EditorsAshraful Alam Khan

MBBS

Md. Mahbubur RahmanMBBS

Members of the Editorial BoardMuhammadul Haque

MBA

A. H. Mahbub AlamM Pharm, PhD

Information AssistanceMd. Masudul Alam

MA

The views expressed in this publication do not necessarily reflect those of its editor or SQUAREPharmaceuticals Ltd. Information in “the SQUARE” may be reprinted or translated to otherlanguages without permission but proper credit must be given to “the SQUARE”.

A P R I L 2 0 0 5 V O L 1 3 N O 2 IN THIS ISSUE:Polycystic OvarySyndrome ... Page 1

Deep VenousThrombosis ... Page 5

Vitiligo ... Page 9

Childhood Asthma ... Page 13

Product Profile- Comet® & Comet XR® ... Page 17

SQUARE in International Business ... Page 19

Medical Breakthrough ... Page 20

ISSN 1681-5552Key title: The SQUARE (Dhaka)Abbreviated key title: SQUARE (Dhaka)

Omar Akramur Rab

“the SQUARE”

olycystic ovary syndrome (PCOS) is the most commonendocrinopathy in women and the most common causeof anovulatory infertility, affecting 5-10% of thepopulation. Interest in PCOS has increased recently withthe realization that this syndrome involves far more thanthe reproductive system. Initially it is called as Stein-Leventhal syndrome after its researchers in the 1930s.PCOS is now recognized to be a metabolic syndromewhich may include hyperinsulinemia, hyperlipidemia,diabetes mellitus, and possibly cardiac disease, as well asthe more conventionally recognized increase in androgenlevels, cosmetic problems, anovulation, infertility,endometrial cancer and obesity. PCOS is generallyunderdiagnosed, and menstrual abnormalities, such ascycles shorter than 21 days or longer than 35 days, areoften associated with the condition. Many young womenwith these disorders are prescribed the oral contraceptivepill, which masks the condition until they try to achievepregnancy.

Diagnostic CriteriaThe diagnostic criteria for PCOS are controversial,diagnosis is generally based on peripubertal onset ofmenstrual problems with clinical or biochemicalhyperandrogenism.

Criteria for PCOS and related disorders :(Criteria of US National Institute of Health)PCOS:❏ Presence of menstrual abnormalities and anovulation❏ Presence of clinical and/or biochemical hyperand-

rogenemia❏ Absence of hyperprolactinemia or thyroid disease❏ Absence of late-onset congenital adrenal hyperplasia❏ Absence of Cushing’s syndrome

Polycystic ovaries:❏ Presence of polycystic ovaries on ultrasound

examination❏ Absence of menstrual or cosmetic problem❏ Absence of biochemical hyperandrogenemia

Idiopathic hirsutism:❏ Presence of excess hair growth❏ Absence of biochemical hyperandrogenemia

A recent consensus workshop held in The Netherlandsduring 1st May 2003 under auspicial of the European

Society for Human Reproduction and Embryology(ESHRE) and the American Society for ReproductiveMedicine (ASRM) proposed a revision of the criteria forthe diagnosis of PCOS, of which 2 out of the following 3would be needed:❏ Menstrual dysfunction – oligomenorrhea and/or

anovulation❏ Clinical and/or biochemical signs of hyperandro-

genism, and❏ Polycystic ovaries on ultrasound examinationExclusions criteria:❏ Congenital adrenal hyperplasia❏ Androgen-secreting tumors❏ Cushing’s syndrome.

PathogenesisThe pathogenesis of PCOS is not very clear. The primarydefect may be insulin resistance leading to hyperinsuli-nemia. In the ovary, the cardinal feature is functionalhyperandrogenism. Circulating concentrations of insulinand luteinising hormone (LH) are usually raised. Thetheca cells are increase in size, hyper-responsive andoverproduce androgens. These androgens are convertedin the ovary to estrogen. The rise in LH levels is thought tobe caused by the relatively high and unchangingconcentrations of estrogens that may alter the control ofthis hormone by the hypothalamic-pituitary axis.

This combination of raised levels of androgens, estrogens,insulin and LH explains the classic PCOS features ofhirsutism, anovulation or dysfunctional bleeding, andglucose metabolism impairment. Paradoxically, althoughthe insulin regulatory molecules on the theca cells areresponsive to insulin, those in the muscle and liver areresistant.

1

A p r i l 2 0 0 5 , V o l 1 3 ; N o 2the SQUAREhealthcare bulletin

P o l ycy s t i c Ova ry Synd romePo l ycy s t i c Ova ry Synd rome

P

▲

Luteinisinghormone

Insulin, insulin-likegrowth factor

Extraovarianandrogen

Ovariansteroidogenesisblock

Dysregulation ofandrogen secretion

Intraovarianandrogen

Follicular atresiaHyperandrogenemia

Ovarian defect in PCOS

Reproductive AbnormalitiesWomen with PCOS may present with the followingabnormalities-❏ Infertility (mean incidence 74%)❏ Menstrual irregularity

◆ Dysfunctional bleeding (DUB), 29%◆ Amenorrhea, 51%

❏ Hyperandrogenism, 69%, and❏ Virilization, 21%.

Anovulation is usually chronic in PCOS and is associatedwith infertility and DUB, such as oligomenorrhea oramenorrhea. The menstrual irregularity typically begins atmenarche and although amenorrhea may occur, the usualpresentation is oligomenorrhea. About 40% of PCOSpatients are present with infertility. If pregnancy isachieved, other reproductive problems, such asmiscarriage, emerge. The miscarriage rate in PCOS isabout 30% of all pregnancies, which is double the rate ofnormal women. The exact mechanism is unknown. Highlevels of LH and androgens have been regarded as a causefor poor reproductive history. The unfavorable endocrineenvironment to which ovarian follicles are exposed could

2P o l y c y s t i c O v a r y S y n d r o m e


be at least partly responsible for a low percentage ofpregnancies, because it affects oocyte quality and lutealphase efficiency. The prevalence of gestational diabetes(GD) in PCOS patients has been reported to be 40-46%.

PCOS and Metabolic SyndromeLong-term health consequences: PCOS patients tend to beobese with abdominal deposition of body fat and insulinresistance. These patients also tend to have hypertension,higher levels of triglycerides, low-density lipoprotein(LDL)- cholesterol, and total cholesterol, with lower highdensity lipoprotein (HDL)- cholesterol. Insulin resistanceis associated with an unfavorable lipid profile.Hyperinsulinemia inhibits lipolysis with a consequentincrease in levels of nonesterified fatty acids (NEFAs).High levels of NEFAs led to increased triglyceride levelsand reduced HDL levels. Elevated plasminogen activatorinhibitor-1 (PAI-1) levels have been reported in obesewomen and lean PCOS patients, and a direct correlationwith insulin resistance. PAI-1 is a potent inhibitor offibrinolysis. Elevated levels of fibrinogen, an independentrisk for developing CVD, has been found in PCOSpatients.

Insulin resistance is recognized as a major risk factor fortype 2 diabetes mellitus. Another risk factor is pancreaticβ-cell dysfunction, which is also found in PCOS,presumably making PCOS patients at increased risk fortype 2 diabetes mellitus. Multiple factors other thaninsulin resistance and β-cell dysfunction, such as obesity,and family history of type 2 diabetes, may contribute toincrease diabetes risk in PCOS.

▲

Facial hirsutism Axillary acanthosis nigricans

Clinical ManifestationsPCOS is a life long condition which may affect at any age, even in the intrauterine period.

Manifestations of PCOS at different ages

Fetal life Peripuberty Adolescence and Adulthood Ageing

Small baby syndrome Exaggerated adrenarche Polycystic ovary syndrome Metabolic syndrome❏ Intrauterine growth ❏ Increased levels of: ❏ Anovulation ❑ Diabetesretardation (IUGR) ◆ Adrenal androgens ❏ Hyperandrogenism ❑ Hypertension

◆ Insulin ❏ Polycystic ovaries ❑ Dyslipidemia❏ Functional ovarian ❏ Obesity (50%) ❑ Increased plasminogen

hyperandrogenism activator inhibitor-1

Leads to Leads to Leads to Leads to Long-term health effects Precocious puberty Reproductive disorders Metabolic effects



The risk of endometrial disease is adversely influenced byseveral factors including obesity, unopposed estrogen,and infertility. All these factors are found in women withPCOS.

InvestigationsHistory and general examination: These are needed toelicit evidence of peripubertal menstrual dysfunction andhirsutism. Gynecological examination is required only toexclude other causes of bleeding and miscarriage. Mildclitoromegaly is not uncommon, but significantenlargement raises the possibility of virilization.

Pelvic ultrasound examination: Transvaginal ultrasound isthe best imaging mode. Endometrial thickness shouldalways be assessed to exclude significant endometrialpathology.

Hormone assays: Measurement of total testosterone ortestosterone adjusted for sex-hormone-binding globulin(SHBG) is helpful to show hyperandrogenemia and to ruleout an androgen-secreting tumor. Diagnosis of PCOSdemands exclusion of late-onset congenital adrenalhyperplasia, thyroid abnormality, hyperprolactinemia,and Cushing’s syndrome.

Glucose testing: Glucose tolerance test is essential toexclude glucose intolerance. Some investigators haverecommended calculating an index of insulin resistancefrom glucose and insulin levels (eg, the homeostasismodel assessment [HOMA] or quantitative insulinsensitivity check index [QUICKI]). Random and fastingglucose levels are usually normal in women with PCOS.

Lipid status: Total and HDL cholesterol and triglyceridelevels should be assessed.

Other investigations: Laparoscopy of the pelvis, computedtomography (CT scan) and magnetic resonance imaging(MRI) are never justifiable for suspected PCOS alone.Endometrial biopsy and hysteroscopy may be required toinvestigate unexplained vaginal bleeding.

Management Management comprises treatment of the presentingsymptoms, as well as any other abnormalities discoveredon investigation. The modality depends on the desire forfertility.

Hirsutism❏ Oral contraceptive pill.

❏ Cosmetic measures: laser electrolysis, bleaching,waxing or shaving.

❏ Oral estrogen and cyproterone acetate (oestradiolvalerate 2 mg daily and cyproterone acetate 50 mg for14 days a month).

❏ Spironolactone (75-200 mg daily); or❏ Other drugs, eg, antiandrogen flutamide or the

antifungal agent ketoconazole.

Response times for drugs can be up to 3 months.

Menstrual dysfunction and endometrial hyperplasia❏ Progestins (eg, medroxprogesterone acetate or

norethisterone); or ❏ Oral contraceptive pill.

Overweight, obesity and glucose intolerance❏ Lifestyle modification❏ Diet❏ Exercise❏ Weight control❏ Oral antidiabetic drugs: metformin

Infertility❏ Lifestyle modification: Weight loss can lead to

resumption of ovulation within few weeks. High-protein diets seem to be as effective as high-carbohydrate diets, provided that fat and total caloriesare comparable. While lifestyle change is difficult tomaintain, women seeking pregnancy are highly

▲

Drugs(eg. corticosteroids,thiazide diuretics)Pregnancy

Ageing

Geneticpredisposition

HyperinsulinemiaIncreased lipid storage

Altered steroidhormone metabolism

Polycystic ovary syndrome:

The new targetfor therapiesin polycysticovary syndrome

Traditional targetfor therapiesin polycysticovary syndrome

AcneHirsutismHyperandrogenism (feeds back to increase insulin resistance)Infertility

Altered lipoprotein andcholesterol metablism

Insulinresistance

Upper abdominalobesity

Lifestyle(eg. lack of exercise,

smoking)

Pathways to insulin resistance and polycystic ovary syndrome

motivated, making this a first-line intervention inoverweight women with PCOS. Longer-term changesin weight are moredifficult to maintain.

❏ Clomiphene citrate:This is an oral estro-gen antagonist thatincreases the con-centrations of FSHand induces folliculargrowth. The initialregimen is 25-50 mgper day for 5 days. Therapy can be monitored byestrogen levels, follicular ultrasound examination andluteal progesterone level (>20 nmol/L). Failure toresponse is associated with high body mass index andhigh androgen levels. Doses up to 200 mg per day canbe used before failure of response is established.Tamoxifen can be used in case of withdrawal ofclomiphene for side effects. Both treatments increasethe risk of multiple pregnancies.

❏ Metformin: Use of insulin-sensitizing drug metforminat doses 500-2500 mg per day gives excellent result inincreasing menstrual cyclicity and pregnancy rate.Recent studies suggest that the drug has efficacy forovulation induction, either as a sole agent or incombination with clomiphene citrate. It has beenwidely used for this purpose, and no specific neonatalcomplications have been described. This drug alsoshows promising result in preventing recurrentmiscarriage and to prevent gestational diabetes.

The new insulin-sensitizer, the “glitazones”– rosiglita-zone and pioglitazone – have been shown to be veryeffective for ovulation induction, but are not approvedfor PCOS. There is greater concern about the effectson the fetus of these drugs compared with metformin,and they should not be used by women trying toconceive.

❏ Gonadotrophin treatment: Ovulation induction withgonadotrophin such as FSH has proved successful butrequires skill and experience to avoid multiplepregnancies and ovarian hyperstimulation syndrome.Low-dose recombinant FSH should be administeredsubcutaneously. Ovarian response should be

monitored by ultrasound examination, and often byestradiol measurement. Human chorionic gonadotro-

phin is given when onefollicle reaches 16-20mm in size. Any morethan two follicles of anappropriate size give therisk of multiple pregnan-cies. Multiple gonadotro-phin cycles may berequired to achieve preg-nancy. This approach ispreferable before more

invasive procedures like in-vitro fertilization.

❏ Surgery to the ovaries: Wedge resection of the ovarieshas been abandoned because of concern about pelvicadhesion, subfertility, and loss of valuable ovariantissue. Ovarian diathermy or laser drilling has beenused in recent years with apparently good results.

❏ In-vitro fertilization: Ovulation induction by a skilledreproductive endocrinologist is preferable to in-vitrofertilization because of the risks of hyperstimulationand multiple pregnancies with the latter procedure.

Long-term managementWomen with PCOS require ongoing surveillance to detectimpaired glucose tolerance, hyperlipidemia, endometrialhyperplasia and consequent complications. Obesewomen, in particular, require regular (annual) glucosetolerance testing because of the potential for rapidprogression from normal to impaired glucose toleranceand diabetes.

Some researchers have suggested prophylactic use ofmetformin in young teenagers and older women to avoidthe problems of the metabolic syndrome. Advice aboutimproved exercise, diet, and lifestyle modification is moreeffective in preventing and treating problems of glucosemetabolism.

References:❑ Medical Journal of Australia. Vol.180, February 02, 2004; 132-37❑ Annals of Internal Medicine. Vol.132, N.12; June 2000; 132:989-93❑ Endocrine Reviews. 24(5); Oct 2003; 633-667❑ Endocrine Reviews. November 23; 2004



the SQUARE

Polycystic ovaries, showing in-creased size & smooth white surfacereflecting thickening of the capsule

Section through polycystic ovary,showing multiple cysts with dia-meter <10 mm arranged around theperiphery of the ovary. The stroma isincreased & the ovary enlarged


EtiopathogenesisThe pathophysiology of DVT is still not clearlyunderstood. Although the cause is multifactorial,Virchow’s triad (stasis, vascular injury, and hyper-coagulability) defines the events that predispose a vein tothe developement of thrombophlebitis. Risk factors orclinical conditions that increase the risk of DVT can beclassified as either increasing the baseline propensity forthrombosis, or precipitating the thrombotic event acutely.

American Society of Hematology proposes a model forthe formation of venous thrombosis. According to themodel, endothelial stimulation or injury results from

5Deep Venous ThrombosisDeep Venous Thrombosis

▲

Swelling in one leg following childbirth was, forcenturies, called "milk leg," because the swelling wasbelieved to be caused by milk retained by mothers whodid not nurse. Others thought it was due to infection orthe blockage of lymph nodes. Eventually, investigationsperformed in the early part of the 1800s showed that theswelling was due to thrombosis in deep veins of the thigh.Today, this type of deep vein thrombosis followingpregnancy, in which the painfully swollen leg appearspale in color, is called phlegmasia alba dolens.

Venous thromboem-bolism (VTE), mani-fested as either deepvenous thrombosis(DVT) or pulmonaryem-bolism (PE), is acommon medicalproblem, occurringeither in isolation oras a complication ofother disease orprocedures. DVT &PE are the majorcause of morbidityand mortality. AcuteDVT affects as manyas 800,000 newpatients per year.Untreated DVT canresult in pulmonaryembolism, a poten-tially fatal outcome.Anticoagulant the-rapy reduces bothmorbidity and mor-tality from venousthrombo-embolism,and early diagnosisis therefore impor-tant. Accurate diag-nosis of deep ve-nous thrombosis mi-nimizes the risk of thromboembolic complications andaverts the exposure of patients without thrombosis to therisks of anticoagulant therapy.

Virchow’s Triad Increased Baseline Propensity for thrombosis Acute Insult

Hypercoagulability Genetic Increased coagulants

Increased coagulants Blood-borne tissue factors

Prothrombin mutation G20210A Malignancy (Trousseau’s syndrome)

Decreased anticoagulants Congestive heart failure

Antithrombin (AT) deficiency Systemic infection

Protein C deficiency Exogenous administration of clotting factors

Protein S deficiency rVIIa

Factor V Leiden rVIII

Acquired Acute loss of anticoagulants

Malignancy Nephrotic syndrome (loss of AT)

Hyperhomocysteinemia Initial warfarin therapy without heparin

Hormone replacement therapy (HRT) /

Oral contraceptive pill (OCT)

Pregnancy (hormone related)

Nephrotic syndrome (loss of AT)

Antiphospholipid syndrome

Increased levels of clotting factors

Direct Vessel Injury Endothelial injury secondary to chemotherapy Intravascular catheters

Hyperhomocysteinemia Trauma

Vasculitis Surgery

Antiphospholipid syndrome

Blood Stasis Age Hospitalization/bed ridden

Obesity Pregnancy (stasis)

Pregnancy (gradual immobility/stasis) Limb paralysis (e.g., stroke, plaster casts)

Sedentarism Right heart failure

Long-haul flights

Vein compression (e.g., enlarged lymph

node)

Potential mechanisms by which various clinical conditions may facilitate DVT


❏ Iliofemoral venous thrombosis can result in cyanosisof the skin (phlegmasia cerulea dolens) or a pale, coolextremity if reflex arterial spasm is superimposed(phlegmasia alba dolens).

DiagnosisA precise diagnosis of DVT by history and physicalexamination is difficult. Diagnostic studies are essentialbecause of the difficulty in diagnosis and because of themorbidity associated with treatment.

Duplex ultrasonography: It is highly sensitive, specific,and reproducible. It is most widely used diagnosticprocedure in the initial evaluation of patients suspected ofhaving DVT. The examination includes both a B modeimage and Doppler flow analysis. Each venous segment isassessed for the presence of thrombosis, indicated byvenous dilation and incompressibility during light probepressure. Doppler findings suggestive of acute thrombosisare absence of spontaneous flow, loss of flow variationwith respiration, and failure to increase flow velocity withdistal augmentation. The criteria for chronic venousthrombosis are less well established. The chronicallyoccluded vein is often narrowed, and there are prominentnearby collaterals. Chronic thrombi are highly echogenic,while acute thrombi are anechoic on the B mode image.Duplex ultrasound is less accurate in detection of calfDVTs and is highly operator-dependent.

Ascending contrast venography: This study is rarely usedbecause it is invasive and exposes the patient to ionizingradiation and the risks of contrast allergy, contrast-induced nephropathy, and phlebitis. Patients in whomdeep venous thrombosis is strongly suspected butultrasound is equivocal are now being referred for

6D e e p V e n o u s T h r o m b o s i s

either blood stasis-induced hypoxia and/ or from directvein wall injury (e.g., trauma). Tissue factor (TF)-bearingmicrovesicles from monocyte/macrophage cells attach toand fuse with stimulated endothelial cells. This interactioninvolves P-selectin glycoprotein ligand 1 (PSGL-1) on themicrovesicle and P-selectin or E-selectin on theendothelium. Transfer of TF to the endothelial cell initiatesthe enzymatic cascade of coagulation reactions, leadingto thrombin generation and fibrin deposition.

Clinical FindingsSymptoms and signsOnly 40 to 50 percent of people with DVT have obvioussigns and symptoms of DVT, and the condition often goesunrecognized. When they do occur, signs and symptomsvary depending on the severity of the condition.Symptomatic patients with deep venous thrombosis maycomplain of:❏ A dull ache❏ Tightness, or❏ Pain in calf or leg, especially when walking

Physical examination may reveal:❏ Slight edema of the involved calf❏ A palpable cord❏ Distension of the superficial collaterals, or❏ Low-grade fever and tachycardia❏ Homans’ sign (pain on passive dorsiflexion of the

ankle) is positive in only 50% of cases

▲

Model of formation of venous thrombosis

Deep venous thrombosis

CoagulationInitiation

P-selectin

E-selectin

PSGL-1

Tissue Factor

Propagation

TF-bearingmicrovesicle

X II

IIa

XI IX X

VIIaXa Xa Va IIa

Fibrin

Fibrinogen

Va XIa IXa VIIIa

II

gadolinium-enhanced magnetic resonance venography.This examination has a sensitivity of 100% and aspecificity of 96% and may provide some informationabout the age of the thrombus.

D-dimer blood test: D-dimer is a marker of endogenousfibrinolysis and should therefore be detectable in patientswith deep-vein thrombosis. Several studies have shownthe D-dimer assay to have a high negative predictivevalue and D-dimer to be a sensitive but nonspecificmarker of DVT.

Other tests: Many of the inherited and acquired causes ofhypercoagulability can be detected by blood tests: ❑ Antithrombin III, protein C, protein S❑ Factor V Leiden ❑ Prothrombin G20210A mutation ❑ DIC screening ❑ Lupus anticoagulant and anticardiolipin antibodies.

Differential diagnosis❑ Localized muscle strain or contusion❑ Achilles tendon rupture❑ Cellulitis❑ Unilateral leg edema- lymphedema, rupture of a Baker

cyst, obstruction of the popliteal vein by a Baker cyst,obstruction of the iliac vein by tumor or fibrosis, orMay-Thurner syndrome (external compression of leftiliac vein by the right common iliac artery)

❑ Bilateral leg edema- heart, liver, or kidney failure, orvena caval obstruction by tumor, retroperitonealfibrosis, or pregnancy.

Complications❑ Pulmonary embolism (PE) ❑ Varicose veins❑ Chronic venous insufficiency

PreventionProphylactic measures may diminish the incidence ofDVT in hospitalized patients. Choice of therapy is dependon the status and individual risk factors of the patients.

Non-pharmacologic measures: DVT can be prevented byreducing venous stasis by several simple maneuvers. 15-20 degree elevation of the foot of the bed encouragesvenous outflow. Slight flexion of the knee is preferable. Afootboard enables the patient to perform leg exercise(ankle flexion and extension) while in bed.

Sitting in a chair for prolonged time in the earlypostoperative period must be avoided. Early ambulance isideal. For reduction of the risk of calf vein thrombosis,graduated compressing stockings and sequentialcompression devices are proven effective measures andare particularly useful in moderate-risk and high-riskpatients in whom anticoagulants are contraindicated.

Anticoagulation: Low dose unfractionated heparin, 5000units subcutaneously twice daily, and low molecularweight heparin (LMWH) e.g., enoxaparin, 30 mgsubcutaneously twice daily, have both been shown toreduce the incidence of postoperative deep veinthrombosis and pulmonary embolism. LMWH appears tobe more effective in the orthopedic surgery patients and isassociated also with a lower risk of bleeding complica-tions. Use of heparin products are contraindicated inpatients with recent craniotomy, intracranial bleeding, orsevere gastrointestinal bleeding. Either medication mustbe withheld 12 hours prior to placement or removal of anepidural catheter to avoid epidural hematoma. Plateletcount should be monitored for early recognition ofheparin-induced thrombocytop-enia, which occurs withpeak incidence at 5-10 days of treatment.

Warfarin is seldom used for perioperative DVTprophylaxis but may be indicated for long-termmanagement of minimally ambulatory patients. Lifetimeanticoagulation with low-dose warfarin or prophylacticvena caval filter placement is considered in patients withhypercoagulable state or paralysis.

TreatmentDeep veinous thrombosis must be treated promptly.Treatment usually requires hospitalization, primarily tofacilitate monitoring of medications. Because DVT occursin post-surgical patients, however, the person mightalready be in the hospital when DVT is diagnosed.

Bed rest: Individuals with DVT usually require bed restuntil symptoms are relieved. The leg should be elevated toa position above the heart to reduce swelling (the foot ofthe bed is elevated about six inches to achieve this). Moistheat may be applied to the affected region to relieve pain.

Compression stockings: compression stockings (alsocalled TED or thrombo-embolic deterrent stockings) arerecommended for the patients who have DVT to reducesymptoms. Compression stockings improve circulation by



▲

providing a graduated pressure on the leg to help returnthe venous blood to the heart.

Anticoagulants: The standard treatment of deep venousthrombosis is systemic anticoagulation with heparin(initial bolus 100 units/kg followed by 10units/kg/h, dosedto a goal partial thromboplastin time of 1.5-2 timesnormal). This reduces the risk of pulmonary embolism anddecrease the rate of thrombophlebitis recurrence by 80%.Systemic anticoagulation does not directly lyse thrombibut stops propagation and allows natural fibrinolysis tooccur.

Warfarin is started after therapeutic heparinization. Thetwo therapies should overlap to diminish the possibility ofa hypercoagulable state, which can occur during the firstfew days of warfarin therapy (because warfarin inhibitssynthesis of the natural anticoagulant proteins C and S).The recommended treatment for the first episode ofuncomplicated DVT is 3-6 months of warfarin. After asecond episode, warfarin is continued indefinitely. Therisk of recurrent DVT is increased markedly in thepresence of factor V Leiden mutations, homozygousactivated protein C resistance, antiphospholipid antibody,and deficiencies of antithrombin III and protein C orprotein S. Lifelong anticoagulation is recommended forthese conditions.

Recently, enoxaparin at therapeutic dose (1 mg/kgsubcutaneously twice daily) is safe and effective alternatefor the treatment of DVT. The drug does not requiremonitoring of its anticoagulant effect because of itspredictable dose-response relationship, so it has beenpromoted for use in outpatient treatment. Unfractionatedheparin inhibits thrombin by complexing thrombin andantithrombin III. The enoxaparin molecule is too small toinhibit thrombin in this way. It inhibits factor Xa activity,which accounts for its lower risk of bleeding complica-tions and thrombocytopenia. It has also demonstrated lessprotein C and S inhibition, less complement activation,and a lower risk of osteoporosis.

Current research efforts are directed toward innovation ofan oral thrombin inhibitor. This is expected to have amore favorable dose-response curve and side-effectprofile than warfarin.

Many studies have evaluated the efficacy of fibrinolyticagents in the treatment of acute DVT. Risk of bleeding

complication is higher with fibinolytic agents and doesnot appear to be reduced by selective catheterization forlocal application. To get effective result, alteplase (a tissueplasminogen activator produced by recombinant DNAtechnology) should be instituted within after clotformation, before extensive fibrin cross-linking can occur.One possible application of alteplase is acute iliofemoralvenous thrombosis complicated by massive extremityedema and cyanosis.

Catheter-directed thrombolysis:A thrombolytic agent is placeddirectly into the thrombus througha catheter to dissolve the throm-bus. Balloon angioplasty: Balloonangioplasty is used to widen thevein after the blood clot has beendissolved.

Stent: A stent may be inserted into a vein to keep the veinopen if it tends to collapse. Once it is in the properlocation, the stent is expanded. Surgery: If an embolus develops, surgery may benecessary to prevent the spread of the clot to the lung.Surgery, however, is performed only as a last resort.Surgery for complications resulting from DVT involves theinsertion of a filter into the inferior vena cava trap anyblood clots headed toward the lungs. The procedure iscalled vena cava interruption.

The most severe cases of DVT may require thrombectomy.The patient is given anticoagulant therapy with heparinduring the surgery, and warfarin for a period of at least sixweeks to three months following the operation.

Prognosis Prognosis is good in most cases, if DVT is diagnosed earlyand treated accurately. Mortality is related to pulmonaryembolism, which occurs in 60% of cases with inade-quately treated proximal lower extremity thrombosis.

Reference: ❑ Deep Venous Thrombosis. American Society of Hematology: Hematology

2004; 439-56❑ Current Medical Diagnosis and Treatment; 43rd Edition; 2004❑ Evaluation of D-Dimer in the Diagnosis of suspected Deep Vein Thrombosis.

N Engl J Med 2003; 349:1227-35.❑ American Academy of Orthopedics Surgeon; 2001



the SQUARE

Catheter-directedthrombolysis

Tunica intima

Catheter

Thrombolyticagent

Thrombus

itiligo is more commonly known as leukoderma, whichis a pigmentation disorder in which melanocytes in theskin, the mucous membranes, and the retina aredestroyed. As a result, white patches of skin appear ondifferent parts of the body. Lesions are often symmetricaland frequently involve the face, hands and genitalia. Thehair can also depigmented. Trauma may induce newlesions. Basically, Vitiligo can hardly be called as adisease but a skin-disorder that has more social thanmedical significance, especially amongst the dark skinnedpeople. Spontaneous repigmentation can occur and oftenstarts around hair follicles giving a speckled appearance.However, repigmentation is rare if a lesion has persistedfor more than 1 year or if the hair is depigmented. Thepsychological consequences of vitiligo can be devastatedespecially in Asian or black African people.

Epidemiology and EtiologyThe vitiligo sufferers are observed all over the world,including the white skin communities. About 1 to 2percent of the world’s population, or 40 to 50 millionpeople, have vitiligo. Ninety-five percent of cases vitiligo

develop before their 40th birthday. However, epide-miologically most cases are recorded in India (8.8%) andMexico. Males and females are affected equally, inclusiveof children age group. It may begin at any age. Childhoodvitiligo is not uncommon.

Vitiligo seems to be more common in people with certainautoimmune diseases. These are hyperthyroidism, hypo-thyroidism, diabetes, adrenocortical insufficiency,

alopecia areata, and pernicious anemia. The reason forthe association between vitiligo and those autoimmunedisorders is still unknown. However, most people withvitiligo have no other autoimmune disease.

The familial incidence is almost 20 to 30%. Vitiligo inidentical twins has been reported.

Some people with vitiligo have reported that a singleevent such as a severe sunburn or an episode of emotionaldistress seems to have triggered their vitiligo. Events of thisnature, however, have not been scientifically proven tocause vitiligo and may simply be coincidences.

There are a number of inherited disorders associated withvitiligo. They include: albinism of the ocular type,autoimmune polyendocrinopathy syndrome, congenitaldeafness with vitiligo and achalasia, dyschromatosissymmetrica hereditaria, ermine phenotype, familialhistiocyctic reticulosis, kabuki syndrome, Letterer-Siwedisease, progressive hemifacial atrophy, progressivevitiligo with mental retardation and urethral duplication,Schmidt syndrome, and the syndrome of spasticparaparesis, vitiligo, premature graying and characteristicfacies.

The abundance of genetic diseases associated with vitiligoclearly reflects the fact that there are a number of genes,which normally govern the development, and well beingof the melanocyte. The precipitating factors have beenidentified as due to pressure of tight clothes (such as onthe waist) or certain occupational hazards such aswearing certain rubber hand gloves. Long term intake ofcertain drugs is found to produce this pigment disorder. Inmany cases, especially in children, often have no cluewhy one develops vitiligo. However like many diseaseconditions, the exact causation yet remains a mystery!

PathogenesisThe cause of vitiligo is not fully known, three principaltheories have been presented about the mechanism ofdestruction of melanocytes in vitiligo. The autoimmunetheory holds that selected melanocytes are destroyed bycertain lymphocytes that have somehow been activatedinternally. The neurogenic hypothesis is based on aninteraction of the melanocytes and the nerve cells. Theself-destruct hypothesis suggests that melanocytes aredestroyed by toxic substances formed as part of normalmelanin biosynthesis. While the immediate mechanism

9


V i t i l i g oV i t i l i g o

V

▲

Stress

Hormonal

Trauma

Genetictendency

Occupational

Drugs

ALTERED IMMUNITY

Vitiligo

for the evolving white macules involves progressivedestruction of selected melanocytes by cytotoxic T cells,other genetically determined cytobiologic changes andcytokines must be involved. Because of differences in theextent and course of segmental and generalized vitiligo,the pathogenesis of these two types must be somewhatdifferent.

HistoryCharacterizations of the onset of vitiligo suggest that thereare both predisposing (genetic) and precipitating(environmental) factors. Important factors in a patient'smedical history include: ❑ Vitiligo in the family❑ Rash❑ Sunburn, or other skin trauma at the site of vitiligo 2 to

3 months before depigmentation started❑ Stress or physical illness❑ Premature graying of the hair (before age 35).

People who develop vitiligo usually first notice whitepatches on their skin. These patches are more common insun exposed areas, including hands, feet, arms, face andlips. Other common areas for white patches to appear arethe armpits and groin and around the mouth, eyes,nostrils, navel, and genitals. It has a tendency to start as asingle spot and gradually grow in size and number. Thespread of the disorder is usually slow and progressive.Symmetrical appearance on both the sides of the body iscommon.

The patches of depigmentation are sharply defined and, inCaucasians, may be surrounded by light brown ‘café aulait’ hyperpigmentation. Some spotty perifollicular pig-ment may be seen within the depigmented patches and issometimes the first sign of repigmentation. Sensation inthe depigmented patches is normal. The course isunpredictable but most patches remain static or enlarge; afew repigment spontaneously.

In addition to white patches on the skin, people withvitiligo may have premature graying of the scalp hair,eyelashes, eyebrows, and beard. People with dark skinmay notice a loss of color inside their mouths.

Physical ExaminationSkin LesionsType : Macules; 5 mm to 5 cm or more in diameter.

Color : Chalk white. Newly developed macules may beoff-white in color; this represents a transitional phase. Thedisease progresses by gradual enlargement of the oldmacules or by development of new ones. Pigmentationaround a hair follicle in a white macule may representresidual pigmentation or return of pigmentation. Confetti-sized hypomelanotic macules also may be observed.Inflammatory vitiligo has an elevated erythematousmargin and may be pruritic; this appears to have nospecial significance.

Shape : convex margins with round, oval, or elongated.Linear or artifactual macules represent the isomorphic or“Koebner” phenomenon.

Distribution : Depigmentation occurs in three generalpatterns. The focal type is characterized by one or several

macules in a single site; thismay be an early evolutio-nary stage of one of theother types in some cases.The segmental type ischaracterized by one orseveral macules in oneband on one side of thebody; this type is associated

rarely with distant vitiligo macules or with furtherevolution of the disease. The most common type isgeneralized vitiligo, characterized by widespread distribu-tion of depigmented macules, often in a remarkablysymmetric array. Typical macules occur around the eyesand mouth and on digits, elbows, and knees, as well as onthe low back and in genital areas. The “lip-tip” patterninvolves the skin around the mouth as well as on distalfingers and toes; lips, nipples, and genitalia (tip of thepenis) may be involved. Extensive generalized vitiligomay leave only a few normally pigmented areas of skin ;this is referred to as vitiligo universalis.

Associated Cutaneous FindingsAt times, vitiligo may associate with one or more of thefollowing conditions:❑ Alopecia areata❑ Premature graying of the hair❑ Lichen planus❑ Psoriasis❑ Halo nevus❑ Ichthyosis

10V i t i l i g o


▲

Vitiligo-affecting different areas offace and throat

There is no increased risk for malignancy in the whiteskin. Skin cancers (all types) appear to be rare. In olderpatients, photoaging may occur in vitiligo macules withlong exposures to sunlight.

General Examination:Vitiligo is not uncom-monly associated withthyroid disease (up to30% of all vitiligo cases,and especially in wo-men), diabetes mellitus(probably less than 5%),pernicious anemia (uncommon but increased risk),Addison’s disease (uncommon), and multiple endocrino-pathy syndrome (rare). Ophthalmologic examination mayreveal evidence of healed chorioretinitis or iritis (probablyless than 10% of all cases). Vision is unaffected. Hearingis normal.

Differential diagnosis❑ Lupus erythematosus❑ Pityriasis alba❑ Piebaldism❑ Pityriasis versicolor alba❑ Chemical leukoderma (history of exposure to certain

phenolic germicides, confetti macules). This is adifficult differential diagnosis

❑ Leprosy (endemic areas, off-white color, anestheticmacules)

❑ Nevus depigmentosus❑ Nevus anemicus❑ Tuberous sclerosis❑ Leukoderma associated with melanoma may be true

vitiligo (may repigment spontaneously, usually ahistory of psoriasis or eczema in the same maculararea), not so sharply defined.

Laboratory and special examinationDiagnosis usually can be established on clinical groundsalone; however, in certain difficult cases, a skin biopsymay be required.

Wood’s lamp examination : Wood’s lamp examination isrequired to evaluate macules, particularly in lighter skintypes, and to identify macules in sun-protected areas in allbut the darkest skin types.

Dermatopathology : Established vitiligo macules shownormal skin except for an absence of melanocytes. Theremay be melanocytes at the margins (normal numbers ofmelanocytes that appear relatively inactive or reducednumbers that are very activated) and a mild lymphocyticresponse. These changes are not diagnostic for vitiligo,however only consistent with it.

Electron microscopy : Electron microscopy has demons-trated other changes in skin affected by vitiligo; theseinclude changes in keratinocytes: spongiosis, exocytosis,basilar vacuopathy, and necrosis. Extracellular granulesand lymphocytes have been seen in the epidermis.

Laboratory studies : T4, TSH (radioimmunoassay), fastingblood glucose, complete blood count with indices(Pernicious anemia), ACTH stimulation test (Addison’sdisease) if suspected.

ManagementTherapy of vitiligo is long, tedious and also veryunsatisfactory, and the patient must be strongly motivated.Treatment has advanced significantly recently, althougholder therapies still retain an important place in themanagement of this therapeutically challenging disease.

If less than 20% of the skin is involved (most cases),topical methoxasalen, 0.1% in ethanol and propyleneglycol or in Acid Mantle cream or Unibase, is used, withcautious exposure to long-wavelength ultraviolet light(UVA), followed by thorough washing and sun avoidance.

With 20-25% involvement, oral PUVA [Psoralen (P) andlong-ware ultraviolet radiation (UVA)] is best. Severephototoxic response (sunburn) may occur with topical ororal psoralens plus UVA. The face and upper chestrespond best, and the fingertips and the genital areas donot respond to this treatment. Newer techniques of usingepidermal autografts and cultured epidermis combinedwith PUVA therapy give hope for surgical correction ofvitiligo.

Potent topical corticosteroids have been advocated fortreatment of vitiligo, with daily use for 10 days followedby 10 days of rest, then repetition. Steroids may initiallyhelp for a very short time, however they have oftendangerous and longer lasting side effects such thinning ofthe skin, dilated blood vessels, bruising, skin colourchanges and hair loss. Vitiligo often flares up much worseafter discontinuing steroids. Long term use of Cortisone

11V i t i l i g o


▲

Vitiligo-affecting hands

can cause liver and kidney disease and worsen psoriasis.

Narrow Band Ultraviolet B (NB-UVB) is a useful and well-tolerated treatment option for patients with moderate tosevere vitiligo. NB-UVB, a light source that emits a verynarrow spectrum of UVB, is the portion of sunlight thatcauses sunburn. The application of Narrow Band UVB byitself can cause regimentation to begin in many patients.The patient applies no drugs either topically or orally. Forthis treatment patient needs simply expose to NarrowBand UVB rays for a relatively short time on a periodicbasis either daily in some cases or 2-4 times a week.Covering areas unaffected by Vitiligo with opaqueclothing or sunscreens will reduce the exposure toneighboring areas.

NB-UVB has an excellent safety profile for use in children.While NB-UVB therapy has been used in Europe since themid-1980s, there has not been any evidence that it causesan increase in skin cancer.

Tacrolimus, the first in a new class of drugs called topicalimmunomodulators (TIMs) shows promise as aninnovative treatment option for the patient with vitiligo.Different new study showed the success with tacrolimusin restoring pigment to affected areas. Efficacy and safetyof the tacrolimus ointment in case of adult and children asa treatment for vitiligo has also been illustrated in differentstudy. Tacrolimus ointment 0.1% is almost as effective asclobetasol propionate 0.05% in inducing repigmentation.A major advantage of tacrolimus is that it is well toleratedwhen used for extended periods.

Pseudocatalase cream plus calcium used as a substitutionfor low catalase levels in the treatment of vitiligo.Repigmentation with pseudocatalase cream PC-KUS canbe achieved in all skin colors and is independent of thepercentage of depigmented skin and the duration of thedisease: First signs of repigmentation can be observedafter 3-4 months. This treatment modality can alsosuccessfully repigment lips, ears and genitals. However,the response on fingers and feet is disappointing. Theremoval of high levels of epidermal H2O2 withNarrowband UVB activated pseudocatalase – PC-KUScoincides with – stabilization of the depigmentationprocess followed by repigmentation. The treatment has noside effects providing the liver function of the affectedindividual is normal. A significant faster initiation of

repigmentation can be induced with the combination ofclimatotherapy together with pseudocatalase PC-KUSover a period of 21 days. First repigmentation occursbetween the day 14-20. This fast repigmentation lasts foran additional 4 months when continued with dailytreatment using Narrowband UVB activatedpseudocatalase PC-KUS.

Sunblocks should be used to prevent burning.Camouflage cosmetics may also be helpful, particularly inthose with dark skin. There is no clinical evidence thatexists anywhere that proves vitamins, homeopathic or aspecial diet can improve, treat or cure vitiligo.

Course and PrognosisVitiligo is a chronic disease. The course is highly variable,but rapid onset followed by a period of stability or slowprogression is most characteristic. Up to 30% of patientsmay report some spontaneous repigmentation in a fewareas particularly areas that are exposed to the Sun. Theabsence of whiteness of the hairs in the area of vitiligo isa good prognostic feature. Rarely is this satisfactory to thepatient. Rapidly progressive or “galloping” vitiligo mayquickly lead to extensive depigmentation. Segmentalvitiligo is a special subset that usually developsprecipitously in one unilateral region, usually does notextend beyond that initial one-sided region, and oncepresent is very stable. The treatment of vitiligo-associateddisease (i.e. thyroid disease) appears to have no impact onthe course of vitiligo.

Reference❑ Dermatology Times, July 1,2004❑ Journal of the American Academy of Dermatology, June 2001❑ Arch Dermatol 2003; 139:651-654❑ Beatpsoriasis.com (12.02.2005)❑ Medline Plus (19.01.2005)❑ US National Vitiligo Foundation, 2003❑ MedicineNet.com 5th April, 2002❑ US NIAMS, May, 2001❑ American Academe of Dermatology’ 2005❑ Dermabest Inc. 2004❑ Color Atlas and Synopsis of Clinical Dermatology, 3rd Edition❑ Hand book of Dermatology and Venerology (Social Hygiene Hand

book)- 2nd Edition ❑ Current Medical Diagnosis & Treatment; 43rd Edition; 2004 ❑ Davidson’s Principles and Practice of Medicine,

19th Edition

12V i t i l i g o


the SQUARE

sthma is a significant and global health-care concernaffecting an estimated 8% of the adult population andpossibly up to 20% of children. Asthma is a chronicinflammatory disorder of the airways characterized byhyperresponsiveness, reversible airflow limitation, andrespiratory symptoms. It is a common morbidity inchildren. It has a potential interference with society interms of morbidity, quality of life (physical activity,education, socialization, and self-esteem) and health carecosts. The prevalence of asthma has increased over thelast 3 decades, and the trends in the incidence of asthmaalso appear to be rising.

Risk Factors Provocative factors for asthma exacerbations have beenwell documented by epidemiologic studies, ranging fromfamilial, allergenic, and environmental, to socioeconomicand psychological factors. The average annual incidenceof physician diagnosed asthma ranged from 0.6 to 29.5per 1000 persons. The highest estimate defined asthma as“2 episodes of cough or wheeze lasting >1-2 weeks andnocturnal symptoms or medication use”.

Host factors❑ Age: The incidence of physician-diagnosed asthma

tends to increase from the 1st year of life throughadolescence, and then decrease into adulthood.

❑ Sex: In general, studies of children found males to beat risk, whereas studies of adolescents or adults foundfemales to be at risk.

❑ History of atopy and parental asthma: Personal atopyor a familial history of asthma is consistent predictorsof incident asthma.

❑ Airway hyperresponsiveness: The risk of eitherdeveloping recurrent wheezing or asthma is increasedamong subjects with reactive airways.

Environmental factors❑ Low birth weight: Low birth weight (<2500 g) as a risk

factor for incident asthma for children <11 years ofage.

❑ Medical factors: Childhood infections, migraineheadache, recurrent abdominal pain, chronicbronchitis increase the risk of incident asthma.

❑ Social factor: Increase exposure to other children,either playground or daycare attendance or havingmore siblings decreases the risk of developing asthma.

❑ Lifestyle factors: Smoking increases the risk ofdeveloping asthma. A positive association betweenhigher BMI and incident asthma among children andadults has been reported.

❑ Indoor exposure: Indoor factors related to incidentasthma include passive exposure to ETS(environmental tobacco smoke), exposure to furredpets, or other allergens, and exposure to dampness.Some studies reported that the proportion of childrenwith incident asthma was lower among those whowere exposed to furred pets during 1st year of life. Asignificant association between exposure to elevatedcockroach allergen levels and incident asthma wasreported.

❑ Outdoor exposure: A significant association betweenoutdoor pollutants (i.e. ozone, particulate matter, andnitrogen dioxide) and incident asthma was found.

❑ Occupational exposure: Working in an environmentwith dust, fumes or smoke resulted in a higher risk ofasthma.

Diagnosis of Asthma in ChildrenA definitive diagnosis of asthma can be difficult to obtainin young children. It is not often possible to measureairway function in order to confirm the presence ofvariable airway obstruction. Asthma should be suspectedin any child with wheezing, ideally heard by a healthprofessional on auscultation, and distinguish from upperairway noises. In schoolchildren, bronchodilatorresponsiveness, PEF (peak expiratory flow) variability ortest of bronchial hyperractivity may be used to confirm thediagnosis.

13


C h i l d h o o d A s t h m aC h i l d h o o d A s t h m a

A

▲

Development of hyperreactivity source, Drazen et al,: J. Exp. Med. 183, 1 (1996)

Allergen

B

M

Allergen

TryptaseLeukotrienes

MBPECP

Leukotrienes

EoIL-3, -5GM-CSF

pep-tide

TH2

IL-4

IL-5

IgE

Othercytokines

Airway-hyper-

reactivity

Allergy tests are helpful in seeking causal factors, and inmaking a general diagnosis of atopy. The presence ofallergy is not essential to the diagnosis of asthma, but itsabsence in a school child with symptoms suggestive ofasthma should prompt consideration of alternativediagnosis.

Indications for Further Investigations in Children❑ Diagnosis unclear or in doubt

❑ Symptoms present from birth or perinatal lungproblem

❑ Excessive vomiting or posseting

❑ Severe upper respiratory tract infection

❑ Persistent wet cough

❑ Family history of unusual chest disease

❑ Failure to thrive❑ Unexpected clinical findings e.g., focal signs in the

chest, abnormal voice or cry, dysphagia, inspiratorystridor

❑ Failure to respond to conventional treatment(particularly corticosteroids > 400 mcg/day)

❑ Frequent use of steroid tablets❑ Parental anxiety or need for reassurance.

Base of the Diagnosis of Asthma in Children❑ The presence of key features and careful consideration

of alternative diagnoses❑ Assessment of the response to trials of treatment, and

ongoing assessment❑ Repeated reassessment of the child, questioning the

diagnosis if management is ineffective.

14C h i l d h o o d A s t h m a


▲

Presenting Features❑ Wheeze ❑ Dry cough❑ Breathlessness ❑ Noisy breathing

Investigation or question to seek❑ Causal factors❑ Exacerbating factors❑ Complications

Differential diagnostictests and/ or trials of

asthma therapy

Detailed history & physical examination❑ Pattern of illness❑ Severity / control❑ Different clues

Is it asthma?

Asthma Action Plan

Diagnosis of asthma in children

No Relevant course of action should be followed Specialist assistance is needed

Probable

Asthma likely

Poor response Good response

Asthma unlikely

Possibly (or comorbidity)

Management

Non-pharmacological managementPrimary prophylaxis: Primary prophylaxis is employedbefore there is any evidence of disease in an attempt toprevent its onset.

❑ Allergen avoidance: There is a strong correlationbetween allergic sensitization to commonaeroallergens and the subsequent development ofasthma. No recommendations of prenatal or postnatalallergen avoidance can be made in relation to primaryprevention of asthma.

❑ Breastfeeding: Breastfeeding should be encouragedand its benefits include a protective effect in relationto early life wheezing.

❑ Microbial exposure: The “hygiene hypothesis”suggests that early exposure to microbial products willswitch off allergic responses preventing allergicdisease like asthma.

❑ Immunotherapy and primary prevention: Preliminaryresults from an outgoing parallel group study usingcontemporaneous untreated children as the controlgroup for pollen immunotherapy in children withallergic rhinitis suggest a lower rate of onset of asthmain the treated group.

❑ Avoidance pollutants: Parents and parents-to-be who

smoke should be advised of the many adverse effectsof smoking on their children, including increasedwheezing in infancy.

Secondary prophylaxis: Interventions made after the onsetof disease to reduce its impact.

❑ Allergen avoidance: Allergen avoidance measures arehelpful in reducing the severity of existing disease.Reducing allergen exposures also reduce the risk ofmorbidity and mortality.

❑ House dust mite control measures: The followings arerecommended to keep the house free from mite:◆ Complete barrier bed-covering systems◆ Removal of carpets◆ Removal of soft toys from bed◆ High temperature washing of bed linen◆ Acaricides to soft furnishing◆ Dehumidification.

Environmental factors❑ Smoking: There is a causal relationship between

parental smoking and lower respiratory illness inchildren up to three years of age. Infants whosemothers smoke are four times more likely to developwheezing illnesses in the first year of life. Smokingcessation must be encouraged as it is good for generalhealth and may reduce asthma severity.



▲

Alternative diagnoses in wheezy children

Clinical clue Possible diagnosis

Perinatal and family historySymptoms present from birth or perinatal lung problem Cystic fibrosis; chronic lung disease; ciliary dyskinesia; developmental anomaly.Family history of unusual chest disease Cystic fibrosis; developmental anomaly; neuromuscular disorder.Severe upper respiratory tract disease Defect of host defense.

Symptoms and signsPersistent wet cough Cystic fibrosis; recurrent aspiration; host defense disorder.Excessive vomiting or posseting Reflux (± aspiration)Dysphagia Swallowing problems (±aspiration)Abnormal voice or cry Laryngeal problemFocal signs in the chest Developmental disease; postviral syndrome; bronchiectasis; tuberculosisInspiratory stridor as well as wheeze Central airway or laryngeal disorderFailure to thrive Cystic fibrosis; host defense defect; gastro-esophageal reflux

InvestigationsFocal or persistent radiological changes Developmental disorder; postinfective disorder; recurrent aspiration; inhaled

foreign body; bronchiectasis; tuberculosis

❑ Air pollution: Changing from high particulate sulfurdioxide (coal burning) environment to a low sulfurdioxide/high diesel particulate environment increasesthe incidence of asthma and atopy.

Weight reduction : Weight reduction is recommended inobese children with asthma, to improve asthma control.

Pharmacological ManagementA stepwise approach aims to abolish symptoms as soon aspossible and to optimize peak flow by starting treatmentat the level most likely to achieve this. Patients shouldstart treatment at the step most appropriate to the initialseverity of their asthma.

The aim is to achieve early control and to maintaincontrol by stepping up treatment as necessary andstepping down when control is good.

Prognosis of Childhood AsthmaTherapeutic decisions, particularly the introduction ofprophylactic treatments may be influenced by thepresence of persistent symptoms, pathophysiology and thenatural history of the disease. If all the factors associatedwith resolution and persistence of asthma presenting inchildhood were not taken into account and every childpresenting with wheeze was treated prophylactically, halfof all children would be treated.

References: ❐ British Guideline on the Management of Asthma; Revised edition;

April 2004❐ Risk factors for asthma incidence. Panminerva Med 2004;46:97-111❐ Improving quality of life in asthmatic children. The Indian J Ped.;

2004:71(12): 1075-78❐ A comparison of the Clinical Characteristics of Children and Adults

with Severe Asthma. Chest/124/4/October 2003.



the SQUARE

* Beclomethasone or equivalent† Higher nominal doses may be required if drug delivery is difficult

STEP 4: PERSISTENT POOR CONTROL

STEP 3: ADD-ON THERAPY

STEP 2: REGULAR PREVENTER THERAPY

patients should be referred to respiratorypediatrician.

Addition of inhaled steroid 200-400 mcg/d*†

In children aged 2-5 years trial of leuketriene receptorantagonist should be considered

In children under 2 years proceeding to step 4should be considered

or leukotriene receptor antagonist if inhaled steroid can't be used

Steroid Inhalation should be started at the dose appropriate to theseverity of disease

STEP 1: MILD INTERMITTENT ASTHMA

Inhalation of short-acting β2 agonist as required

Summary of stepwise management in children less than 5 years

STEP 5: CONTINUOUS OR FREQUENT USEOF ORAL STEROIDS

Daily use of steroid tablet in lowest dose providingadequate controlHigh dose inhaled steroid at 800 mcg/d* should be maintainedPatient should be referred to respiratory Pediatrician

STEP 4: PERSISTENT POOR CONTROL

Steroid inhalation should be increased up to 800 mcg/d*

STEP 3: ADD-ON THERAPY

2. Assessment of control of asthma:a. Good resposne to LABA- continuation of LABAb. Benefit from LABA but control still inadequate- continuation of LABA &

inhaled steroid dose should be increased to 400 mcg/d* (if not already onthis dose)

c. No response to LABA- LABA should be stopped and steroid inhalation 400 mcg/d*. If control still inadequate, trial of other therapies should be inistiituted, e.g. leukotriene receptor antagonist or SR theophylline.

1. Long-acting β2 agonist (LABA) inhaler should be added

STEP 2: REGULAR PREVENTER THERAPY

Inhaled steroid 200-400 mcg/d* should be added (other preventer drug if inhaled steroid can't be used) 200 mcg is an appropriate starting dose for many patients

Steroid Inhalation should be started at the dose appropriate to the severity of disease

STEP 1: MILD INTERMITTENT ASTHMA

Inhalation of short-acting β2 agonist as required

* Beclomethasone or equivalent

Summary of stepwise management in children aged 5-12 years

omet® (metformin hydrochloride tablets)

omet XR® (metformin hydrochloride extended release tablets)

CompositionComet® 500 : Each film coated tablet contains metformin

hydrochloride BP 500 mg. Comet® 850 : Each film coated tablet contains metformin

hydrochloride BP 850 mg.Comet XR® 500 : Each extended release tablet contains

metformin hydrochloride BP 500 mg.

PharmacologyMetformin is an antihyperglycemic agent that improves glucosetolerance in patients with type 2 diabetes, lowering both basaland postprandial plasma glucose. Metformin decreases hepaticglucose production, decreases intestinal absorption of glucose,and improves insulin sensitivity by increasing peripheralglucose uptake and utilization. Unlike sulfonylureas, metformindoes not produce hypoglycemia in either patients with type 2diabetes or normal subjects and does not causehyperinsulinemia.

Indications and UsageComet® and Comet XR® tablets are oral antihyperglycemicdrugs used in the management of type 2 diabetes. Comet® 500 mg and 850 mg tablets and Comet XR® 500 tablets,as monotherapy, are indicated as an adjunct to diet and exerciseto improve glycemic control in patients with type 2 diabetes ormay be used concomitantly with a sulfonylurea or insulin.

Dosage and AdministrationDosage of Comet® or Comet XR® 500 must be individualized onthe basis of both effectiveness and tolerance. The maximumrecommended daily dose of Comet® in adults is 2550 mg and2000 mg in pediatric patients (10-16 years of age); themaximum recommended daily dose of Comet XR® in adults(≥17 years) is 2000 mg.Comet® should be given in divided doses with meals whileComet XR® 500 should generally be given once daily with theevening meal. Comet® or Comet XR® 500 should be started at alow dose, with gradual dose escalation, both to reduce GI sideeffects and to permit identification of the minimum requireddose. During treatment initiation and dose titration, fastingplasma glucose should be monitored. Thereafter, HbA1C shouldbe measured at intervals of approximately three months. Short-term administration of Comet® or Comet XR® 500 may besufficient during periods of transient loss of control in patientsusually well-controlled on diet alone.

PrecautionPregnant mothers : Pregnancy Category B. Metforminshould not be used during pregnancy unless clearlyneeded.

17


Product Profile- Comet® & Comet XR®Product Profile- Comet® & Comet XR®

CC

Nursing mothers: May cause hypoglycemia in nursinginfants. Pediatric use: The safety and effectiveness of metforminimmediate release tablets for the treatment of type 2diabetes have been established in pediatric patients ages10 to 16 years. Safety and effectiveness of metforminextended release tablets in pediatric patients have notbeen established.Geriatric use: The drug should only be used in patientswith normal renal function.

ContraindicationsContraindicated in patient with known hypersensitivity tometformin, patients with renal impairment, CCF, acute orchronic metabolic acidosis including diabeticketoacidosis. The drug should be temporarily discontinued in patientsundergoing radiologic studies involving intravascularadministration of iodinated contrast materials.

Side EffectsDiarrhea, nausea/vomiting, flatulence, asthenia,indigestion, abdominal discomfort, headache, etc.

WarningsThe reported incidence of lactic acidosis in patientsreceiving metformin is very low (approximately 0.03cases/1000 patient-years).

Drug InteractionFurosemide: In single-dose, furosemide increases themetformin plasma and blood Cmax by 22% and bloodAUC by 15%, without any significant change in renalclearance.Nifedipine: Nifedipine appears to enhance theabsorption of metformin. Others: Certain drugs tend to produce hyperglycemia.These drugs include the thiazides and other diuretics,corticosteroids, phenothiazines, thyroid products,estrogens, oral contraceptives, phenytoin, nicotinicacid, sympathomimetics, calcium channel blockingdrugs, and isoniazid.

Storage ConditionThe medicine should be preserved in a cool and dryplace, protected from light and moisture.

How SuppliedComet® 500 : Box containing 10 x 10 Comet® 500

tablets in blister pack.Comet® 850 : Box containing 5 x 10 Comet® 850

tablets in blister pack.Comet XR® 500: Box containing 5 x 10 Comet XR® 500

tablets in blister pack. the SQUARE

18


T e s t Y o u r s e l fT e s t Y o u r s e l f

Test YourselfTest Yourself

Dr. Amin Md. Kamrul Alam MBBSRoom No. 303, NICVD Sher-E-Bangla Nagar, Dhaka

Dr. Farhana Afroz (Jue) MBBSMedical OfficerGreenland HospitalUttara, Dhaka

Dr. Mohammad Nasir Uddin MBBSMedical OfficerIslami Bank Hospital24/B, Outer Circular RoadMotijheel, Dhaka

Dr. Ferdous Alam MBBSMedical Officer, Desh ClinicDhap Jail Road, Rangpur

Dr. Kohinoor Parveen MBBSMedical OfficerShushastho, BRACDupchanchia, Bogra

Dr. (Flt Lt) Md. Masud ImranMedical SquadronBAF, Kurmitola Air BaseDhaka Cantonment

Dr. Milton MBBS324, Pinku HostelRajshahi Medical College HospitalRajshahi

Dr. Md. Nazmul Kabir MBBSRoom No. 8, Dr. Mizan HostelChittagong Medical college Hospital

Dr. Satyajit Roy MBBSMedical Officer, Medicine Dept.BBMH, CSTC, Foy’s Lake, PahartaliChittagong

Dr. Ummey Zahira Popy MBBSInternee Doctor, Surgery Dept.Moulana Bhasani Medical CollegeUttara, Dhaka

Correct answers of the 'Test Yourself - 18’1. c 2. b & d 3. a & c 4. b & d 5. a & c 6. b & d

1. All the points mentioned below are correct for "Vitiligo" except:a. Lesions are often asymmetrical and frequently involve face,

hand and genitals.b. Epidemiologically most cases are recorded in India & Mexico.c. There is no familial incidence of Vitiligo.d. Tacrolimus shows promise in the treatment of Vitiligo.

2. All the followings are true for "DVT" except:a. Only 40 to 50 percent of patients with DVT have obvious signs

and symptoms.b. Achilles tendon rupture, cellulitis are the only differential

diagnosis of DVT.c. Warfarin must be started prior to therapeutic heparinization.d. The most severe cases of DVT may require thrombectomy.

3. All the followings are correct for "Childhood Asthma" except:a. Asthma affects about 20 percent of child population around the

world.b. Dry cough, breathlessness are the only presenting features in

childhood asthma.c. The presence of allergy is not essential to the diagnosis of

asthma.d. Low birth weight babies are in increased risk of developing

asthma.

4. The following features are true for "PCOS" except:a. It affects 5 to 10 percent of the population.b. PCOS patients tend to obese and insulin resistant.c. The miscarriage rate in PCOS is about 20 percent of all

pregnancies.d. Metformin gives excellent result in PCOS.

5. All the following points are true for "Comet® (MetforminHydrochloride)" except:a. Comet® is used in the patient 10 years of age and above.b. Comet XR® must be swallowed whole and never crushed or

chewed. c. Comet XR® is used in the patient 20 years of age and older.d. Comet® should be taken with meals.

6. All the following points are true for "DVT" except:a. Blood stress, vascular injury and hypertrophy are collectively

known as Virchow's triad. b. Varicose veins, pulmonary embolisms are among the

complications of DVT.c. Acute DVT affects as many as 600,000 new patients per year.d. Enoxaparin at therapeutic dose is safe and effective alternative

treatment of DVT.

The following are the 10 winners of the “Test Yourself -18”; they have been selected through lottery.

Congratulations from “the SQUARE” Editorial Board

Soon our officials will be

visiting you with a token of our appreciation

19SQUARE in International BusinessSQUARE in International Business

North Korean Ambassador to Bangladesh HE Mr. Wun Song Mo visitedSQUARE’s manufacturing plant-2 on January 9, 2005. The Ambassador washighly impressed on SQUARE’s quality commitment & formulation technology.

A delegation from Asian Productivity Organization recently visited SQUARE’smanufacturing unit-2. They were briefed on the operation and differenttechnical aspects during the visit.

A high level French business delegation visited SQUARE’s manufacturingfacility during their recent tour to Bangladesh.

SQUARE’s partner in Tanzania visited SQUARE’s manufacturing unit-1 duringtheir recent tour to Bangladesh.

The Chairman and the Managing director of SQUARE Pharmaceuticals Ltd. visited SQUARE’s pavilion during the Asia Pharma Expo 2005held from 15 to 18 February at Dhaka.


Thermal Scans for Arthritis DetectionA device developed to scan computer circuit boards fordefects is now being used to detect early signs of arthritis.New technology gives a chance to see something anormal X-ray can't. Using thermal imaging, researcherscan tell if someone has early signs of arthritis in the hands.The thermal scanner detects temperature differences.Inflamed joints are warmer-the first sign of arthritis. Thethermal scanner issensitive enough todetect differences of atenth of a degree intemperature.

The researchers hopethat if arthritis can beidentified earlier, thenthe doctors have amuch easier chance oftreating it and preventing those late-stage X-ray changes.

Researchers say thermal scanning for arthritis couldbecome commonplace within five years. They also saythermal technology could also help evaluate theeffectiveness of arthritis treatments.

Source: Ivanhoe.com.

Synthetic Paste for Tooth Decay!Treating early tooth decay could become easier and lesspainful! Researchers in Japan have developed a newsynthetic tooth enamel that can repair early tooth decaywithout the need for drillings and fillings. The crystallinewhite paste can reconstruct enamel without removing thedecayed area. It repairs small cavities and helps preventnew ones. Dentists usually treat cavities by removing thedecayed area and filling the hole with a resin or metalalloy. But it is not ideal for small cavities because healthytooth is also removed to make the filling stick. Thescientists tested the new paste on early decay in a lowerpremolar tooth. After examining the tooth with anelectron microscope they found the paste integrated withthe tooth's natural enamel.

But the researchers warned the paste should not comeinto contact with the gums because it could causeinflammation due to its high concentration of hydrogenperoxide.

Source: Reuters Limited.

Camera Phone Diagnoses Leg Wounds!There's another use for those new cell phones that comecomplete with cameras: diagnosing chronic legulceration. Swiss researchers who used the phonecameras to send pictures of wounds to specialists inremote locations say doctors felt fairly comfortablediagnosing the wounds from the photos.

The study involved 52 patients with 61 chronic leg ulcerswho were seen in an outpatient clinic. Investigators had aphysician on site diagnose the wounds, then sent photosof the wounds to two other physicians at remote locationsto get their assessment of the wounds as well. Overall, theremote physicians were able to diagnose the wounds in82% of the cases. Agreement between the variousphysicians was high, suggesting the cell phone photoscould accurately convey the information doctors need tomake a diagnosis.

The researchers plan to conduct additional studies to seehow similar teleconsultations could impact patient careunder routine conditions. Source: Archives of Dermatology, 2005

New CT Scanner for Heart Disease DiagnosisA new heart scanner recently installed at Johns HopkinsMedicine has the potential to revolutionize the diagnosisof heart disease. The CT scanner, known as a 64-slicecomputerized axial tomography scanner, allowsphysicians to obtain very detailed images of the heart andits surrounding structures in 5 to 10 seconds. It iscomparable in quality to the coronary angiogram.Because of its speed, the new CT scanner can be usedbefore patients are stabilized to rapidly diagnose heartattacks and other conditions.

The Hopkins scanner is only the second of its kind in theUnited States. The other is in Boston, Mass.

Until now, the highest resolution CT scanner was a 32-slice machine. Operating at twice the resolution, the newscanner may make CT scanning a first-line diagnosticchoice for the detection and treatment of heart attack andcoronary artery disease. Currently, CT scans are usuallyperformed only when necessary. The number of slices ismeasured by how many x-ray detectors are included inthe machine. The greater the number of detectors, thegreater the resolution of the resulting scan. Source: HealthCentersOnline

20


M e d i c a l B r e a k t h r o u g hM e d i c a l B r e a k t h r o u g h

the SQUARE

Thermal scans showing temperaturedifferences

Camlodin®

PlusAmlodipine 5mg + Atenolol 50 mg

The Fixed-dose combination as recommended by JNC and 1999 WHO-ISH guidelines

Reduces systolic and diastolic blood pressure effectively

Significantly improves the exercise time and decreases the frequencyof ischemic episodes in angina

Safe and well tolerated

Lesser cost of therapy

Starting with combination therapy may be the best way to get hypertensivepatients’ blood pressure down to goal levels.

American Heart Association

Ticamet®

125 & 250Salmeterol 25 µg & Fluticasone propionate 125 µg/puff; 120 puffsSalmeterol 25 µg & Fluticasone propionate 250 µg/puff; 120 puffs

Metered Dose Inhaler

Treats both constriction and inflammation of the airways at the sametime.

Salmeterol relaxes the bronchial smooth muscle & attenuatesallergen-induced bronchial hyper-responsiveness.

Fluticasone reduces the inflammation & swelling of airways.

Makes asthmatics breathe easy

Living life free from pain

®

Ketorolac tromethamine USP

Torax 10 mg tablet10 mg/ml injection30 mg/ml injection

Moderate to severe acute painRenal colicCancer painMusculoskeletal pain

Postoperative painManagement of

Effective in


Production PharmaScope

Medical Services Department, SQUARE PHARMACEUTICALS LTD. Corporate Headquarters, SQUARE CENTRE 48, Mohakhali Commercial Area, Dhaka-1212, Tel : 8827729 - 38, 8817729 - 38, Fax : 880 -2-882 8608 / 882 8609E-mail : [email protected], Web Page : http://www.squarepharma.com.bd, Omar Akramur Rab <[email protected]>

&

Documents

the SQUARE-Q V13 N 2 · 2018-02-20 · enous Thrombosis (DVT)" which is more commonly also itiligo", the condition can be cosmetically disfiguring andaffects 0.1-2% of the world's