MIDEAST,AFRICA DRUG IMPORTERS SEEKS DISCOUNT AFTER PRICE CUTS IN INDIA

Many small and medium drug makers are under pressure from key buyers in foregien markets to cut prices in line with government mandated price reduction in India. In may the government's drug price control order set price caps on 151 of 348 essential  medicines amid resistance from the industry . Now the importers in the gulf region as well as some African nations are demanding that they be given drugs at reduced price too.

As a result , many small and medium Indian drug makers are finding it difficult to execute export orders . India exported medicines worth $1 billion to the gulf and over $2.6 billion to the African regions in 2012 - 13 the total value of drug exported this year was $14.5 billion "we can understand the compulsion of Indian government to reduce  medicine prices for domestic consumers, but the fact is that it is affecting our exports " says PV Appaji director general of pharmaceutical export  promotion council.

Rajesh Madan, executive director of Delhi based Medicamen biotech said client in Saudi Arabia and Ethiopia are asking that they be given discount for drugs such as Amoxicillin , Ampicillin and Ibuprofen "They are demanding that the export price should not be more than what they are in India " he said . This demand would be difficult for Indian drug companies to meet as there are more compliance and packaging requirements for exports . Under the new DPCO, Prices of essential  drugs  have gone down by as much as 60% . While  large Indian companies with deep pockets have the ability to cut prices , smaller manufactures are finding it difficult to meet the demands " We are currently unable to quantify the exact impact of price revision on our bottom line ..... we urge the government to initiate measure to safeguard Indian pharma exports " said BR Sikri , managing director  of next wave India , a Himachal Pradesh based drug manufacturer 

A march report by Alpen Capital on the gulf Pharmaceutical industry estimated the total market size in the region at $8.5 billion in 2012  with Saudi Arabia having a lions share at about 59% followed by united Arab Emirates at over 18% "the demand from the gulf cooperation council to reduce price is probably the consequence of the drug price standardization mechanism that is to be introduced in GCC countries  by 2014 " said Utkarsh Palnitkar , head of pharma and life science  division at KPMG India. a senior official in the union  commerce ministry said the government is considering measure to safegaurd indian drug exports .

well I dnt see any point by the countries to reduce the export price in their case and this will surely affect the Indian pharma export....................

Asthama : Nice guidance

An expert panel of the National Institutes of Health, the National Asthma Education and Prevention Program (NAEPP), has provided the following working definition of asthma:

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli.

Because asthma is a heterogeneous disease triggered by a variety of inciting agents, there is no universally accepted simple classification. Nevertheless, it is customary to classify asthma into two major categories based on the presence or absence of an underlying immune disorder:

1.     Extrinsic asthma, in which the asthmatic episode is typically initiated by a type I hypersensitivity reaction induced by exposure to an extrinsic antigen. Three types of extrinsic asthma are recognized: atopic asthma, occupational asthma (many forms), and allergic bronchopulmonary aspergillosis (bronchial colonization with Aspergillus organisms followed by development of immunoglobulin E [IgE] antibodies). Atopic asthma is the most common type of asthma; its onset is usually in the first two decades of life, and it is commonly associated with other allergic manifestations in the patient as well as in other family members. Serum IgE levels are usually elevated, as is the blood eosinophil count. This form of asthma is believed to be driven by the T_H2 subset of CD4+ T cells.

2.     Intrinsic asthma, in which the triggering mechanisms are nonimmune. In this form, a number of stimuli that have little or no effect in normal subjects can trigger bronchospasm. Such factors include aspirin; pulmonary infections, especially those caused by viruses; cold; psychological stress; exercise; and inhaled irritants such as ozone and sulfur dioxide. There is usually no personal or family history of allergic manifestations, and serum IgE levels are normal. These patients are said to have an asthmatic diathesis.

ETIOLOGY:-

Asthma is at least a partially heritable complex syndrome that requires a gene-by-environment interaction for phenotypic expression. Epidemiologic studies strongly support the concept of a genetic predisposition to the development of asthma.10 Genetic factors account for 35% to 70% of the susceptibility.

List of Agents and Events Triggering Asthma

Respiratory infection

Respiratory syncytial virus (RSV), rhinovirus, influenza,

parainfluenza, Mycoplasma pneumonia

Allergens

Airbone pollens (grass, trees, weeds), house-dust mites, animal

danders, cockroaches, fungal spores

Environment

Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke,

wood smoke

Emotions

Anxiety, stress, laughter

Exercise

Particularly in cold, dry climate

Drugs/preservatives

Aspirin, NSAIDs (cyclooxygenase inhibitors), sulfites, benzalkonium

chloride, β-blockers

Occupational stimuli:

Bakers (flour dust); farmers (hay mold); spice and enzyme workers; printers (arabic gum); chemical workers (azo dyes, anthraquinone, ethylenediamine, toluene diisocyanates, polyvinyl chloride); plastics, rubber, and wood workers (formaldehyde, western cedar, dimethylethanolamine, anhydrides)

PATHOPHYSIOLOGY:-

ACUTE INFLAMMATION

Inhaled allergen challenge models contribute most to our understanding of acute inflammation in asthma.14 Inhaled allergen challenge in allergic patients leads to an early-phase allergic reaction that, in some cases, may be followed by a late-phase reaction. The activation of cells bearing allergen-specific IgE initiates the early-phase reaction. It is characterized primarily by the rapid activation of airway mast cells and macrophages. The activated cells rapidly release proinflammatory mediators such as histamine, eicosanoids, and reactive oxygen species that induce contraction of airway smooth muscle, mucus secretion, and vasodilatation.14 The bronchial microcirculation  has an essential role in this inflammatory process. Inflammatory mediators induce microvascular leakage with exudation of plasma in the airways.14 Acute plasma protein leakage induces a thickened, engorged, and edematous airway wall and a consequent narrowing of the airway lumen. Plasma exudation may compromise epitheepithelial integrity, and the presence of plasma in the lumen may reduce mucus clearance.14 Plasma proteins also may promote the formation of exudative plugs mixed with mucus and inflammatory and epithelial cells. Together these effects contribute to airflow obstruction. The late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation and involves the recruitment and activation of eosinophils, CD4+ T cells, basophils, neutrophils, and macrophages. 14 There is selective retention of airway T cells, the expression of adhesion molecules, and the release of selected proinflammatory mediators and cytokines involved in the recruitment and activation of inflammatory cells.14 The activation of T cells after allergen challenge leads to the release of T-helper cell type 2 (Th2)–like cytokines that may be a key mechanism of the late-phase response.14 The release of preformed cytokines by mast cells is the likely initial trigger for the early recruitment of cells. This cell type may recruit and induce the more persistent involvement by T cells.14 The enhancement of nonspecific BHR usually can be demonstrated after the late-phase reaction but not after the early-phase reaction following allergen or occupational challenge.

CHRONIC INFLAMMATION

In asthma, all cells of the airways are involved and become activated. Included are eosinophils, T cells, mast cells,

macrophages, epithelial cells, fibroblasts, and bronchial smooth muscle cells.

EPITHELIAL CELLS

Bronchial epithelial cells traditionally have been considered as a barrier, participating in mucociliary clearance and removal of noxious agents. However, epithelial cells also participate in inflammation by the release of eicosanoids, peptidases, matrix proteins, cytokines, and nitric oxide (NO). Epithelial cells can be activated by IgE-dependent mechanisms, viruses, pollutants, or histamines. In asthma, especially fatal asthma, extensive epithelial shedding occurs. The functional consequences of epithelial shedding may include heightened airways responsiveness, altered permeability of the airway mucosa, depletion

of epithelial-derived relaxant factors, and loss of enzymes responsible for degrading proinflammatory neuropeptides.

EOSINOPHILS

Eosinophils play an effector role in asthma by release of proinflammatory mediators, cytotoxic mediators, and cytokines.15 Circulating eosinophils migrate to the airways by cell rolling, through interactions with selectins, and eventually adhere to the endothelium through the binding of integrins to adhesion proteins (vascular cell adhesion molecule 1 [VCAM–1] and intercellular adhesion molecule 1 [ICAM–1]). As eosinophils enter the matrix of the membrane, their survival is prolonged by interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). On activation, eosinophils release inflammatory mediators such as leukotrienes and granule proteins to injure airway tissue.

LYMPHOCYTES

Mucosal biopsy specimens from patients with asthma contain lymphocytes, many of which express surface markers of inflammation. There are two types of T-helper CD4+ cells. Type 1 T-helper (Th1) cells produce IL-2 and interferon-γ (IFN-γ ), both essential for cellular defense mechanisms. Th2 cells produce cytokines (IL-4, -5, -6, -9, and -13) that mediate allergic inflammation. It is known that Th1 cytokines inhibit the production of Th2 cytokines, and vice versa.

MAST CELLS

Mast cell degranulation is important in the initiation of immediate responses following exposure to allergens.2 Mast cells are found throughout the walls of the respiratory tract, and increased numbers of these cells (three- to fivefold) have been described in the airways of asthmatics with an allergic component. Once binding of allergen to cell-bound IgE occurs, mediators such as histamine; eosinophil and neutrophil chemotactic factors; leukotrienes C4, D4, and E4; prostaglandins; platelet-activating factor; and others are released from mast cells.

ALVEOLAR MACROPHAGES

The primary function of alveolar macrophages in the normal airway is to serve as “scavengers,” engulfing and digesting bacteria and other foreign materials. They are found in large and small airways, ideally located for affecting the asthmatic response.

FIBROBLASTS AND MYOFIBROBLASTS

Fibroblasts are found frequently in connective tissue. Human lung fibroblasts may behave as inflammatory cells on activation by IL-4 and IL-13. The myofibroblast may contribute to the regulation of inflammation via the release of cytokines and to tissue remodeling.

ADHESION MOLECULES

An important step in the inflammatory process is the adhesion of the various cells to each other and the tissue matrix to facilitate infiltration and migration of these cells to the site of inflammation. To promote this, cell membranes express a number of glycoproteins, or adhesion molecules. Adhesion molecules have additional functions involved in the inflammatory process aside from promoting cell adhesion, including activation of cells and cell-cell communication, and promoting cellular migration and infiltration.

REMODELING OF THE AIRWAYS

Acute inflammation is a beneficial, nonspecific response of tissues to injury and generally leads to repair and restoration of the normal structure and function. In contrast, asthma represents a chronic inflammatory process of the airways followed by healing. The end result may be an altered structure referred to as a remodeling of the airways.16 Repair involves replacement of injured tissue by parenchymal cells of the same type and replacement by connective tissue and its maturation into scar tissue. In asthma, the repair process can be followed by complete or altered restitution of airways structure and function, presenting as fibrosis and an increase in smooth muscle and mucus gland mass.

MUCUS PRODUCTION

The mucociliary system is the lung’s primary defense mechanism against irritants and infectious agents. Mucus, composed of95%water and 5% glycoproteins, is produced by bronchial epithelial glands and goblet cells.7 The lining of the airways consists of a continuous aqueous layer controlled by active ion transport across the epithelium in which water moves toward the lumen along the concentration gradient. Catecholamines and vagal stimulation enhance the ion transport and fluid movement. Mucus transport depends on the viscoelastic properties of the mucus. Mucus that is either too watery or too viscous will not be transported optimally. The exudative inflammatory process and sloughing of epithelial cells into the airway lumen impair

mucociliary transport. The bronchial glands are increased in size and the goblet cells are increased in size and number in asthma. Expectorated mucus from patients with asthma tends to have a high viscosity.

C L I N I C A L PRESENTATION

CHRONIC AMBULATORY ASTHMA

GENERAL

Asthma is a disease of exacerbation and remission, so the patient may not have any signs or symptoms at the time of exam.

SYMPTOMS

The patient may complain of episodes of dyspnea, chest tightness, coughing (particularly at night), wheezing, or a whistling sound when breathing. These often occur in association with exercise, but also occur spontaneously or in association with known allergens.

SIGNS

Expiratory wheezing on auscultation, dry hacking cough, or signs of atopy (allergic rhinitis and/or eczema) may occur.

LABORATORY

Spirometry demonstrates obstruction (FEV1/FVC less than 80%) with reversibility following inhaled β2-agonist administration (at least a 12% improvement in FEV1).

OTHER DIAGNOSTIC TESTS

A fall in FEV1 of at least 20% following 6 minutes of near maximal exercise. Elevated eosinophil count and lgE concentration in blood. Elevated FeNO (greater than 12ppb). Positive methacholine challenge (PC20 FEV1 less than 12.5 mg/mL).

ARF: a review

ARF

a condition in which a previously normal serum creatinine rises by 0.5 mg/dL, or an absolute increase in serum creatinine of >1 mg/dL in a patient with previous chronic kidney disease (CKD).

In the clinical setting, ARF is classified in a variety of ways. Classifying ARF by daily urine output can be useful. Anuria is defined as a urine output of <50 mL/d, oliguria is when the daily urine output is 50 to 450 mL/d, and nonoliguria occurs when the patient can make >450 mL of urine per day.

EPIDEMIOLOGY

ARF is a common condition in the general population, with an annual incidence of approximately 200 cases per million population per year.2 The incidence rate is higher in hospitalized patients, 5% of whom may require RRT (Table 42–1).7 The highest incidence of ARF is in hospitalized patients in the intensive care unit. Depending on the definition used, ARF develops in 2% to 25% of patients in intensive care units.8−10 Many patient-specific factors cause a predisposition to the development of ARF. In nonhospitalized patients, ARF is often druginduced. Common causes of drug-induced ARF include nonprescription

nonsteroidal anti-inflammatory drugs (NSAIDs), prompting the FDA to convene an advisory committee to re-examine labeling

of these products.11 This drug class alone may be responsible for 500,000 to 2,500,000 cases of nephrotoxicity in the United States per year.

OUTCOMES

The development of ARF is one of the most serious events that can happen to a hospitalized patient, regardless of the reason for hospitalization. In patients admitted for cardiac surgery, the mortality risk is seven- to eightfold higher if the patient develops ARF.19 Patients who develop ARF following administration of intravenous radiocontrast dye and requiring dialysis have twice the mortality rate of similar patients receiving radiocontrast dye who do not experience an increase in their serum creatinine values.13 The outcome of a patient with ARF predominantly depends on the cause of the condition. In general, higher mortality rates are seen in conditions that result in hypoxia to the kidney causing acute tubular necrosis (ATN; 60%) or cortical necrosis (100%) compared to the lower mortality associated with autoimmune ARF causes like glomerulonephritis (9% to 25%), vasculitis (45%), or interstitial nephritis (13%).2 Similarly, postrenal causes like obstructive ARF tend to have lower mortality rates (27%), ostensibly because these obstructions can be surgically repaired before permanent damage can be done to the kidney. Other patient factors influence ARF outcomes. Understandably, those patients with higher severity of illness have higher mortality rates than those who do not.18 Critically ill patients with ARF due to sepsis have mortality rates that are significantly

higher than those of patients who develop ARF for other reasons (74% vs. 45%).

ETIOLOGY:

Prerenal renal failure Functional acute renal failure Acute intrinsic renal failure Postrenal renal failure (obstruction)

Systemic hypoperfusion Isolated renal hypoperfusion Vascular Glomerular Acute tubular necrosis Acute interstitial nephritis Bladder outlet obstruction Ureteral (bilateral or unilateral with solitary functioning kidney) Renal pelvis or tubules

Intravascular volume depletion Dehydration Hemorrhage CHF Liver disease Nephrotic syndrome Overdiuresis Bilateral renal artery stenosis (unilateral renal artery stenosis in solitary kidney) Emboli Cholesterol Thrombotic Medications: Cyclosporine ACEIs NSAIDs Hypercalcemia Hepatorenal syndrome Vasculitis Polyarteritis nodosa Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Emboli Cholesterol Thrombotic Systemic lupus erythematosus Poststreptococcal glomerulonephritis Antiglomerular basement membrane disease Ischemic Hypotension Vasoconstriction Exogenous toxins Contrast dye Heavy metals Drugs (amphotericin B, aminoglycosides, etc.) Endogenous toxins Myoglobin Hemoglobin Drugs Penicillins Ciprofloxacin Sulfonamides Infection Streptococcal Prostatic hypertrophy Improperly placed bladder catheter Cervical cancer Retroperitoneal fibrosis Crystal deposition Oxalate Indinavir Sulfonamides Acyclovir Tumor lysis syndrome

PATHOPHYSIOLOGY

A basic knowledge of renal function facilitates the understanding of how ARF manifests itself clinically. The most logical approach to understanding renal function is to divide the kidney into its four basic component parts: the vasculature, the glomeruli, the tubules, and the interstitium surrounding the other three component parts.

1.RENAL VASCULATURE

The kidney is a highly vascular organ with blood vessels ranging from the very large (renal arteries) to the very small capillaries providing blood to each individual glomerulus. Obstruction of the renal artery will result in an increase in serum creatinine, hematuria, and proteinuria, but obstruction of smaller vessels will only cause infarction of the downstream parenchyma. If this area is small, no change in serum creatinine will occur. Smaller vessels may be obstructed with cholesterol emboli, vascular

lesions, or platelet plugs, all of which will present as isolated decreased perfusion of the glomeruli. The serum creatinine frequently is increased since the lesions are usually diffuse. However, the urinalysis most commonly will be normal since the kidney itself is not ischemic and the glomeruli are not involved. The urinary indices suggest prerenal azotemia (i.e., a low urine sodium concentration and a low fractional excretion of sodium) in the absence of systemic hypotension or a decrease in effective blood volume. The urine volume may or may not be diminished. However, the onset of oliguria secondary to diffuse arterial lesions within the kidney, such as that which occurs with hemolytic uremia syndrome, denotes a poor chance for salvage of renal function.

2.GLOMERULI

The glomerulus consists of an enlargement of the proximal end of the renal tubule to incorporate a vascular tuft connecting the afferent and efferent arterioles (Fig. 42–1). The production of glomerular ultrafiltrate is predominantly dependent on the transcapillary hydrostatic pressure (dictated by the afferent and efferent arteriolar resistance) and the glomerular surface area. Afferent arteriolar tone is determined primarily by the local levels of angiotensin II (which induces vasoconstriction)

and prostaglandins (which induce vasodilation). Efferent arteriolar tone is predominantly determined by the local concentration

of angiotensin II. Pathophysiologic processes and medications that result in alterations of the afferent and efferent arteriolar tone (i.e., systemic hypotension, hypercalcemia, or use of ACEIs, angiotensin II receptor blockers, or NSAIDs) reduce glomerular ultrafiltrate production as a result of a decrease in glomerular hydrostatic pressure. Under these conditions, the serum creatinine will rise, the urine sediment will be normal, and the urine indices will suggest prerenal azotemia. However, the urinary solutes may or may not be maximally concentrated, depending on the circulating level of antidiuretic hormone

that is necessary to maximally concentrate the urine. Damage to the glomerular capillary tuft (e.g., acute glomerulonephritis) results in a decline in the production of glomerular ultrafiltrate as a result of a decrease in glomerular capillary surface area. Under these conditions the serum creatinine rises and the urinalysis is significant for hematuria and proteinuria because of the increased permeability of the damaged glomerular capillaries. Proteinuria exceeding 3 g/day is often referred to as nephrotic range proteinuria. Prolonged heavy proteinuria secondary to glomerular damage may result in the nephritic syndrome.

3.RENAL TUBULE

Under normal conditions, approximately 180 L of glomerular ultrafiltrate are produced per day, the vast majority of which must be reabsorbed by the renal tubules to maintain homeostasis. Clinically, the renal tubule can be divided into three major sections: the proximal tubule, Henle’s loop, and the distal nephron, which includes the distal tubule, the cortical collecting tubule, and the medullary collecting ducts. In the proximal tubule, approximately 60% to 70% of the filtered load of water and solute is isovolemically reabsorbed, as is the vast majority of filtered amino acids, glucose, and bicarbonate. In addition to its other functions, Henle’s loop is responsible for a significant portion of the total reabsorption of potassium, calcium, and magnesium, as well as for generating the osmotic gradient within the kidney that is necessary for the concentration of urinary solutes. Damage

to this portion of the nephron results in wasting of potassium and magnesium by the kidney and an inability of the kidney to concentrate the urine. The medullary portions of Henle’s loop are very sensitive to ischemia secondary to hypoperfusion. Consequently, in severe prerenal azotemia with renal hypoperfusion, there may be a loss of urinary concentrating ability despite the continued presence of a low urinary sodium concentration and a low fractional excretion of sodium. Major functions of the distal nephron include the regeneration of bicarbonate, the excretion of acid (hydrogen ion), the secretion of

potassium, and the reabsorption of water. Damage to this portion of the nephron may present as significant acidemia and either hypoor hyperkalemia, depending on the mechanism of injury.

4.INTERSTITIUM

The interstitium of the kidney provides the structural support for the kidney and serves to provide the environment in which concentrating gradients can be established. In addition, the interstitium of the kidney plays a major role in urinary ammonia handling. To facilitate the regeneration of bicarbonate and the excretion of acid by the distal nephron, the kidney utilizes ammonia as a urinary buffer. When the interstitium of the kidney is damaged (e.g., in acute allergic interstitial nephritis), the concentrating gradient within the kidney may be dissipated and ammonia handling disrupted. Consequently, patients presenting with acute interstitial nephritis frequently are unable to concentrate the urinary solutes. The urinalysis may show mild proteinuria

and hematuria. However, the striking finding on microscopic examination of the sediment is the presence of numerous WBCs and WBC casts.

C L I N I C A L PRESENTATION OF ACUTE RENAL FA I L U R E

GENERAL

Outpatients often are not in acute distress; hospitalized patients may develop ARF after a catastrophic event

SYMPTOMS

Outpatient: Change in urinary habits, weight gain, or flank pain

Inpatient: Typically ARF is noticed by clinicians before it is noticed by the patient

SIGNS

Patient may have edema; urine may be colored or foamy.

Vital signs may indicate orthostatic hypotension in volumedepleted patients

LABORATORY TESTS

Urine and blood chemistries may determine prerenal cause complete blood cell count (CBC) and differential rules out

infectious causes Urine microscopy may reveal casts, WBCs, RBCs, and eosinophils

OTHER DIAGNOSTIC TESTS

Renal ultrasound or cystoscopy may be needed to rule out obstruction; renal biopsy reserved for difficult diagnoses

TREATMENT

NONPHARMACOLOGIC

In situations in which administration of a nephrotoxin cannot be avoided, such as when radiocontrast dye is to be administered, nonpharmacologic therapies can be employed to prevent ARF. The key to nonpharmacologic ARF prevention is the elimination of the patient’s risk factors to the degree that is possible. The best-studied examples of this are the interventions used to maximize renal perfusion when radiocontrast dye is administered. Adequate hydration and sodium loading prior to radiocontrast dye administration have been shown to be beneficial therapies. A trial comparing infusions of 0.9% NaCl or 5% dextrose with 0.45% NaCl administered prior to radiocontrast dye infusion conclusively demonstrated that the normal saline was superior in preventing ARF.26 The intravenous solution infusion rate used in this study was 1 mL/kg per hour beginning the morning that

the radiocontrast dye was going to be given, and all subjects were encouraged to drink fluids liberally as well. The benefits of 0.9% NaCl infusions have been found in similar studies,27 suggesting this regimen should be used in all at-risk patients who can tolerate the sodium and fluid load.

PHARMACOLOGICAL

HYDARTION, MANNITOL, LOOP DIURETIC, DOPAMINE, CCBs, THEOPHYLLINE, ACETYLCYSTEINE, FENOLDOPAM, INSULIN.