New Drug of the day : Romiplostim

New Pharmacological Drug Classes Introduced in 2008 

Romiplostim is an fusion protein (peptibody) that contains two identical single-chain subunits, each consisting of a human immunoglobulin IgG1 Fc domain covalently linked to a peptide containing two TPO receptor-binding domains. 

The drug is licensed for the treatment of thrombocytopenia in patients with refractory chronic immune thrombocytopenic purpura and acts as a thrombopoietin (TPO) receptor agonist to activate intracellular transcriptional pathways leading to increased platelet production.

As a class, TPO receptor agonists are thought to increase the risk for development of bone marrow fibrosis and may increase the risk for hematologic malignancies. 

Romiplostim is administered as a subcutaneous injection with the dose adjusted to the lowest dose necessary to reduce the risk of bleeding and achieve a platelet count ≥50 x 109/L. A maximum weekly dose of 10 mcg/kg is recommended with therapy discontinued if the platelet count does not increase sufficiently within 4 weeks of therapy. Hyporesponsiveness or failure to maintain a platelet response may signal the development of neutralizing antibodies. 

Discontinuation of therapy poses a risk for worsening of thrombocytopenia below baseline, with subsequent hemorrhage. Patients receiving romiplostim must be monitored prior to initiation of therapy, frequently during treatment, and for 2 weeks following cessation of therapy.

New Drug of the day : PLERIXA

New Pharmacological Drug Classes Introduced in 2008 

Plerixa started out as an investigational anti-retroviral drug for the treatment of AIDS. An unexpected finding of increased CD34+ hematopoietic stem cell counts in the peripheral blood of subjects exposed to the drug eventually lead to its licensing for use in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection prior to autologous transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma.

Plerixa is an inhibitor of the CXCR4 chemokine receptor. 

CXCR4, is normally responsible for ‘‘homing’’ (anchoring) stem cells in the bone marrow.¹⁶ Plerixa antagonizes the interaction between CXCR4 and its cognate ligand, stromal cell-derived factor-1α. Plerixa works synergistically with G-CSF and is given after "priming" with 4 daily doses of G-CSF. Plerixa is administered subcutaneously, in a dose of 0.24 mg/kg (up to 40 mg), approximately 11 hours prior to an apheresis session, in conjuction with additional daily G-CSF, for up to 4 consecutive days. 

Approximately 1/2 of non-Hodgkins lymphoma patients receiving plerixa will achieve a yield >5 x 10⁶ CD34+ cell harvests after 2 apheresis sessions. 

Data for patients with multiple myeloma suggests that approximately 75% will achieve a yield >6 x 10⁶ CD34+ cell harvests after 2 apheresis sessions. Plerixa is primarily eliminated by the kidneys. Drug-drug interactions may result from coadministration with drugs that reduce renal function or compete for active tubular secretion. (See Figure 4.) (CID: 16727404) 

The most common adverse reactions reported in patients who received plerixa in conjunction with G-CSF and aphresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, vomiting, abdominal pain, hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, hypoesthesia, constipation, dyspepsia, and musculoskeletal pain. 

New Drug of the day : Methylnaltrexone

New Pharmacological Drug Classes Introduced in 2008 

Methylnaltrexone is a peripherally acting μ-opioid receptor antagonist FDA approved for the treatment of refractory opioid-induced constipation in patients with advanced illness (e.g., cancer, AIDS) who are receiving palliative care.

Administered subcutaneously no more frequently than once per day, methylnaltrexone stimulates laxation within 4 hours in approximately 60% of patients. 

Clinical experience confirms a much more rapid onset of action in patients who are opioid tolerant. Methylnaltrexone is a quaternary amine derivative of naltrexone with a limited ability to penetrate into the central nervous system. Side effects are largely extensions of normal gastrointestinal functions: abdominal pain, flatulence, nausea, and diarrhea. The drug is a weak CYP2D6 inhibitor with no known drug-drug interactions. Methylnaltrexone undergoes hepatic metabolism; however, N-demethylation to naltrexone is not thought to be a significant pathway.

Renal excretion of unchanged drug is the dominant route of elimination. The usual dose of methylnaltrexone is 8-12 mg, depending on body weight. Therapy for longer than 4 weeks in the target population of patients with terminal illness is unstudied. Methylnaltrexone was investigated as a treatment for postoperative ileus, but with disappointing results.

New Drug of the day : C1 inhibitor

New Pharmacological Drug Classes Introduced in 2008 

C1 inhibitor : is licensed for the routine prophylaxis against angioedema attacks in patiets with hereditary angioedema (HAE). Application for licensure as a treatment for acute angioedema attacks is pending.

High Anion Gap Acidosis

High Anion Gap Acidosis

Mnemonic is MUD-PILES:

 

M : methanol

U : uremia (renal failure)

D : diabetic ketoacidosis

P : paraldehyde

I  : Iron, Isoniazid

L : Lactic Acidosis.

E : ethylene glycol, ethanol.

S : salicylates

Normal anion gap acidosis : Mnemonic

Normal anion gap acidosis

 

Mnemonic USED CAR:

 

U : uterosigmoidostomy

S : saline administration (in the face of renal dysfunction)

E : endocrine (Addisons, spironolactone, triamterene, amiloride,

primary hyperparathyroidism)

D : diarrhea

 

C : carbonic anhydrase inhibitors

A : ammonium chloride

R : renal tubular acidosis

 

    OR

RAGE:

 

R : renal tubular acidosis, respiratory acidosis

A : acetazolamide, ammonium chloride

G : GI (diarrhea, enteroenteric fistula, ureterosigmoidostomy)

E : endocrine (same as above endocrine list)

 

New Drug of the day : Eltrombopag

New Pharmacological Drug Classes Introduced in 2008 

Eltrombopag is an orally available non-peptide thrombopoietin (TPO) receptor agonist licensed for the treatment of thrombocytopenia in patients with refractory chronic immune thrombocytopenic purpura. 

Eltrombopag is considered a second-generation thrombopoietin agent that does not lead to the development of TPO-neutralizing antibodies. Administration of eltrombopag produces a dose-dependent rise in platelet counts via JAK2 and STAT5 signaling pathways. 

The drug is a hydrazone compound and carries a black box warning regarding hepatotoxicity. As a class, TPO receptor agonists are thought to increase the risk for development of bone marrow fibrosis and may increase the risk for hematologic malignancies. Eltrombopaq may also promote the development of cataracts.

New Drug of the day : Alvimopan

New Pharmacological Drug Classes Introduced in 2008 

Alvimopan : is a peripherally acting μ-opioid receptor antagonist indicated to accelerate gastrointestinal tract recovery following bowel surgery. Use of the drug beyond 7 days is not recommended because of adverse findings related to cardiovascular events and cancer rates .

Alvimopan is a zwitterion with a relatively high molecular weight (461 Da) and low lipophilicity; these physical characteristics hinder penetration of the drug into the central nervous system and account for the predominantly peripheral action.

On average, post-operative patients receiving alvimopan recover GI function 17 hours earlier than patients given placebo. While a faster recovery logically translates to a reduction in the length of hospitalization due to postoperative ileus, the clinical and economic significance of the improved outcome remains unproven.

During pre-marketing clinical trials, the most common adverse reactions among bowel resection patients receiving alvimopan were anemia, dyspepsia, hypokalemia, back pain, and urinary retention. Vigorous gastrointestinal side effects (including abdominal pain, nausea, vomiting, and diarrhea) can be expected when opioid-tolerant patients are given alvimopan, so patients who have taken opioids for the 7 consecutive days immediately prior to surgery should not be considered candidates for the drug.

The oral bioavailability of alvimopan is low (~6%). 

An active metabolite is formed in the gut by intestinal microflora. Since both the parent and metabolite are p-glycoprotein substrates, clinically significant drug interactions may surface with strong p-glycoprotein inhibitors (e.g., verapamil, cyclosporine, amiodorone, itraconazole, quinine, spironolactone, quinidine, diltiazem, and bepridil). 

Biliary secretion is the primary pathway of elimination for unabsorbed alvimopan and the metabolite formed in the gut is eliminated in the feces and urine as unchanged metabolite, the glucuronide conjugate, and other minor metabolites. 

The half-life of alvimopan and the gut metabolite ranges from 10 to 18 hours. The drug accumulates approximately 10-fold in patients with severe hepatic impairment, thereby precluding administration to this group.

New Drug of the day : Lacosamide

Lacosamide, a "functionalized" amino acid, was licensed for adjunctive therapy of partial-onset seizures. Lacsamide modulates sodium channels and also binds to collapsin response mediator protein 2 (CRMP2). CRCMP2 is involved in neuronal differentiation, axonal outgrowth and possibly epileptogenesis³ 

References :- 

(see 11th edition of Goodman & Gilman, pages 501-525).

1. Rogawski MA. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 2006;69(3):273-94. [PMID: 16621450] 

2. Johannessen Landmark C, Johannessen SI. Pharmacological management of epilepsy: recent advances and future prospects. Drugs 2008;68(14):1925-39. [PMID: 18778117] 

 3. Perucca E, Yasothan U, Clincke G, et al. Lacosamide. Nat Rev Drug Discov 2008;7(12):973-4. [PMID: 19043448] 

New Drug of the day : Sancuso®

A transdermal formulation of Granisetron - 5-HT3 blocker, was licensed for the prevention of nausea and vomiting in patients receiving emetogenic chemotherapy 

(see 11th edition of Goodman & Gilman, page 1001-1003).

Clinical mnemonic for MCC MERKEL CELL CARCINOMA

A recent study presented a mnemonic for the clinical features associated with Merkel cell carcinoma:AEIOU. This study found that 89% of 62 Merkel cell carcinoma cases exhibited at least three of the five features listed below. If a lesion exhibits at least three of these features, suspicion of MCC should increase and biopsy be considered. In particular, a lesion that is red or purple, rapidly growing, but non-tender should be of concern.

Asymptomatic/non-tender: 88%

Expanding rapidly: 63%

Immune suppressed: 8%

Over age 50: 90%

Ultraviolet light exposed site: 81%

In January of 2008, a new polyomavirus was reported to be present in MCC tumors. This virus, named the Merkel cell polyomavirus (abbreviated MCV or MCPyV) was discovered by extensive sequencing of MCC tumor RNA. Initially, MCPyV DNA was reported to be present in 8 of 10 MCC tumors as compared to only 1 of 15 skin controls. This strong association of the virus with MCC has been confirmed by numerous other studies that in aggregate have now found MCPyV to be present in a much greater percentage of MCCs than basal cell carcinomas, squamous cell carcinomas, melanomas, or normal skin samples.

Lymphovascular invasion and growth pattern hold prognostic significance Merkel cell carcinoma

Lymphovascular invasion (LVI) was associated with poorer outcome. Presence of LVI was defined by tumor emboli within vascular spaces outside the tumor boundary, as visible on a standard hematoxylin/eosin stained slide. Persons with MCC tumors with detectable LVI had a worse overall survival as compared to those with tumors without LVI (71% vs. 98% survival at 2 years, p<0.001).

An infiltrative tumor growth pattern was associated with poor outcomes as compared to MCC tumors with a nodular growth pattern. Well-circumscribed tumors were considered “nodular” and those with rows, trabeculae, or single cells penetrating the dermis deemed “infiltrative”; tumors that exhibited both features were considered “infiltrative.” 2-year survival for MCCs with an infiltrative pattern was 72% as compared to 93% for well-circumscribed tumors.

pgmeenotes by dv

pgmeedoubts@gmail.com

Hepatic Zonal Necrosis

TYPES OF HEPATIC ZONAL NECROSIS

I) Centilobular / Centrizonal Necrosis -

    a) Cardiac failure / Shock.

    b) CCl4 - Carbon Tetra Chloride.

    c) Chloroform Toxicity.

    d) Viral Hepatitis.

    e) Halothane Hepatitis (~1/35,000)

II) Peripheral Zonal Necrosis --> Necrosis around portal tracts.

     a) Eclampsia.(PIH)

     b) Phosphorus Poisoning.

III) Mid-zonal Necrosis --- RARE

       Seen in Yellow Fever.

New Drug of the Day :Iobenguane I-123

Iobenguane I¹²³ is a radiolabeled norepinephrine (NE) mimetic with a chemical structure similar to guanethedine. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues such as the adrenal medulla, salivary glands, heart, liver, spleen, lungs, and tumors derived from the neural crest. Radiolabeled iobenguane was licensed for use as an adjunct to other tests for the diagnosis of pheochromocytoma and neuroblastoma.

(see 11th edition of Goodman & Gilman, page 164).

Chromoblastomycosis

Chromoblastomycosis (chromomycosis) 

- is a subcutaneous mycotic infection caused by traumatic inoculation by any of five recognized fungal agents that reside in soil and vegetation. All are dematiaceous fungi, having melaninized cell walls: 

1.Phialophora verrucosa - flask-shaped phialides with cup-shaped collarettes.

2. Fonsecaea pedrosoi

3. Rhinocladiella aquaspersa - lateral or terminal conidia from a lengthening conidiogenous cell—a sympodial process.

4. Fonsecaea compacta

5.Cladophialophora (Cladosporium) carrionii - branching chains of conidia by distal (acropetalous) budding. 

The infection is chronic and characterized by the slow development of progressive granulomatous lesions that in time induce hyperplasia of the epidermal tissue.

The agents of chromoblastomycosis are identified by their modes of conidiation. In tissue they appear the same, producing spherical brown cells (4–12 um in diameter) termed muriform or sclerotic bodies that divide by transverse septation. Septation in different planes with delayed separation may give rise to a cluster of four to eight cells.

Pathogenesis & Clinical Findings

The fungi are introduced into the skin by trauma, often of the exposed legs or feet. Over months to years, the primary lesion becomes verrucous and wart-like with extension along the draining lymphatics. Cauliflower-like nodules with crusting abscesses eventually cover the area. Small ulcerations or "black dots" of hemopurulent material are present on the warty surface. 

Rarely, elephantiasis may result from secondary infection, obstruction, and fibrosis of lymph channels. Dissemination to other parts of the body is very rare, though satellite lesions can occur due either to local lymphatic spread or to autoinoculation. Histologically, the lesions are granulomatous and the dark sclerotic bodies may be seen within leukocytes or giant cells. (Copper Penny Bodies are seen in Chromoblastomycosis if you remember).

Diagnostic Laboratory Tests

Specimens of scrapings or biopsies from lesions are placed in 10% KOH and examined microscopically for dark, spherical cells. Detection of the sclerotic bodies is diagnostic of chromoblastomycosis regardless of the etiologic agent. Tissue sections reveal granulomas and extensive hyperplasia of the dermal tissue.

Specimens should be cultured on inhibitory mold agar or Sabouraud's agar with antibiotics. The dematiaceous species is identified by its characteristic conidial structures, as described above. There are many similar saprophytic dematiaceous molds, but they differ from the pathogenic species in being unable to grow at 37 °C and being able to digest gelatin.

Treatment

Surgical excision with wide margins is the therapy of choice for small lesions. Chemotherapy with flucytosine or itraconazole may be efficacious for larger lesions. Local applied heat is also beneficial. Relapse is common.

Ref : Jawetz.

pgmeenotes by dv.

Hydrogen Sulfide: Potential Help for ED !!!

The stench of rotten eggs seems an unlikely aphrodisiac. But new research suggests that a foul-smelling gas could someday become the target of new drugs for erectile dysfunction.

Hydrogen sulfide is present in raw natural gas and in the odor of rotting eggs. Our bodies also produce tiny quantities of hydrogen sulfide, but the gas was long thought to be only a toxic by-product of metabolism.

Research early this decade revealed that many animals actually use hydrogen sulfide to help expand blood vessels. Chemicals that create these expansions in blood flow are called vasodilators.

In previous experiments in mice and monkeys, injecting hydrogen sulfide opened blood vessels and improved erections. But the same chemical pathways weren't yet proven to function in people.

The same enzymes that produce hydrogen sulfide in animals were present and functional in human tissue. The chemical reactions that produce hydrogen sulfide were generally the same, too. The scientists concluded that hydrogen sulfide does likely contribute to erections in men, just as in animal studies.

Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease

Background Percutaneous coronary intervention (PCI) involving drug-eluting stents is increasingly used to treat complex coronary artery disease, although coronary-artery bypass grafting (CABG) has been the treatment of choice historically. Our trial compared PCI and CABG for treating patients with previously untreated three-vessel or left main coronary artery disease (or both).

Methods We randomly assigned 1800 patients with three-vessel or left main coronary artery disease to undergo CABG or PCI (in a 1:1 ratio). For all these patients, the local cardiac surgeon and interventional cardiologist determined that equivalent anatomical revascularization could be achieved with either treatment. A noninferiority comparison of the two groups was performed for the primary end point — a major adverse cardiac orcerebrovascular event (i.e., death from any cause, stroke, myocardial infarction, or repeat revascularization) during the 12-month period after randomization. Patients for whom only one of the two treatment options would be beneficial, because of anatomical features or clinical conditions, were entered into a parallel, nested CABG or PCI registry.

Results Most of the preoperative characteristics were similar in the two groups. Rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (17.8%, vs. 12.4% for CABG; P=0.002), in large part because of an increased rate of repeat revascularization (13.5% vs. 5.9%, P<0.001);> was not met. At 12 months, the rates of death and myocardial infarction were similar between the two groups; stroke was significantly more likely to occur with CABG (2.2%, vs. 0.6% with PCI; P=0.003).

Conclusions CABG remains the standard of care for patients with three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year. (ClinicalTrials.gov number, NCT00114972)

http://content.nejm.org/cgi/content/full/360/10/961?query=TOC

Blood Glucose Management for Type 2 Diabetes Reviewed

Specific key clinical recommendations, and their accompanying level of evidence rating, are as follows:

• Patients with impaired glucose tolerance should receive counseling and education regarding weight loss and physical activity (level of evidence, A).
• In patients with type 2 diabetes, the only medication proven to reduce mortality rates is metformin (level of evidence, A).
• Acarbose appears to be associated with a lower risk for CVD events (level of evidence, B).
• Oral agents should be continued initially when insulin is added to a regimen of oral medication. Long-acting insulin should be used at first, with initial dosage usually 10 units/day or 0.17 to 0.5 units/kg/day, and it should be titrated in increments of 2 units approximately every 3 days (level of evidence, C).

Metformin, a biguanide, is considered a first-line agent and has been shown to reduce progression from glucose intolerance to type 2 diabetes and to reduce mortality rates in patients with type 2 diabetes. The mechanisms of action of metformin are to decrease hepatic glucose output and sensitize peripheral tissues to insulin. To prevent 1 case of type 2 diabetes, the number needed to treat with metformin is 13.9.

Am Fam Physician. 2009;79:29-36.

New Drug of the day : Rufinamide

Rufinamide, a presumed sodium channel modulator, was licensed for use as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome.

(for further : see 11th edition of Goodman & Gilman, pages 501-525).

Mnemonic : Helminth Eggs Floating in Saturated Salt Solution

Mnemonic : Helminth Eggs Floating in Saturated Salt Solution

From AIIMS 1993 May

Mnemonic : 'FATEH' or 'HATE - Fertilized eggs of Ascaris'

1. Hymenolepis nana.

2. Ancylostoma duodenale

3. Trichuris trichura.

4. Enterobius vermicularis.

5. Fertllized eggs of Ascaris.

CAUSES OF HYPERCALCEMIA

CAUSES OF HYPERCALCEMIA
Harrison 17th, AIIMS Nov 2007 Q

Excessive PTH production

Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma)

Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency)

Ectopic PTH secretion (very rare)

Inactivating mutations in the CaSR (FHH)

Alterations in CaSR function (lithium therapy)

Hypercalcemia of malignancy

Overproduction of PTHrP (many solid tumors)

Lytic skeletal metastases (breast, myeloma)

Excessive 1,25(OH)2D production

Granulomatous diseases (sarcoidosis, tuberculosis, silicosis)

Lymphomas

Vitamin D intoxication

Primary increase in bone resorption

Hyperthyroidism

Immobilization

Excessive calcium intake

Milk-alkali syndrome

Total parenteral nutrition

Other causes

Endocrine disorders (adrenal insufficiency, pheochromocytoma, VIPoma)

Medications (thiazides, vitamin A, antiestrogens)

Note: CaSR, calcium sensor receptor; FHH, familial hypocalciuric hypercalcemia; PTH, parathyroid hormone; PTHrP, PTH-related peptide.

Additions:-

**William's Syndrome causes hypercalcemia d/t increased sensitivity to Vitamin D, it is also called as Idiopathic Hypercalcemia of Infancy.

**Increased Bone turnover has also been mentioned for Vitamin A Intoxication and for Thiazides.

pgmeenotesby dv.