Sorafenib

HCC tumors are generally chemoresistant, and only one
drug—sorafenib, a multikinase inhibitor—
is currently approved for advanced HCC patients.

Drugs Licensed in 2008 with Mechanisms Similar to Previously Approved Drugs

Generic Name	Brand Name	Pharmacology	2008 FDA Approved Indication	Pharmacologically Similar Agents
Bendamustine	Treanda	alkylating agent	Treatment of chronic lymphocytic leukemia	busulfan, carmustine, chlorambucil, cyclophosphamide, ifosfamide, melphalan
Certolizumab	Cimzia	tumor necrosis factor inhibitor	Management of Chron's disease

Table: New Pharmacological Drug Classes Introduced in 2008

Pharmacologic Class	First to be Marketed in the U.S.	FDA Approved Indication
C1 inhibitor	C1 inhibitor(CinryzeR)	Routine prophylaxis against angioedema attacks in patients with hereditary angioedema
CXCR4 chemokine receptor inhibitor	plerixa (MozobilR)	Mobilization of granulocyte-colony stimulating factor induced hematopoietic stem cells to the peripheral blood prior to collection

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.

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).

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).

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).

Preliminary Evidence Favors Ustekinumab in Psoriatic Arthritis

February 12, 2009 — Ustekinumab significantly reduces signs and symptoms of psoriatic arthritis and diminishes skin lesions in patients with active psoriatic arthritis, including those with psoriasis affecting 3% or more body surface area, according to results of a phase 2, double-blind, randomized, placebo-controlled, crossover study published online today in The Lancet. The drug was well tolerated, with a similar incidence of adverse events and infections compared with placebo up to week 12 (the double-blind portion of the study).

MORE INFO

It is a laboratory-manufactured monoclonal antibody directed against interleukins IL-12 and IL-23.

What is Nitisinone?

Used for treatment of

1. Hereditary Tyrosinemia Type 1 (HT-1)
2. Alkaptonuria ( Less useful)

Hereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the
final enzyme in the tyrosine catabolic pathway.


Mechanism of Action of Nitisinone

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme
upstream of FAH in the tyrosine catabolic pathway . By inhibiting the normal
catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the
catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1,
these catabolic intermediates are converted to the toxic metabolites succinylacetone and
succinylacetoacetate, which are responsible for the observed liver and kidney toxicity.
Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation
of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

Since nitisinone inhibits catabolism of tyrosine, use of this drug can result in elevated
plasma levels of this amino acid. Treatment with nitisinone, therefore, requires
restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity
associated with elevated plasma levels of tyrosine



Link : More information of Nitisinone at FDA page

Newer Medicines 3: 31-41

31. Omapatrilat: Inhibits both ACE and Neutral Endopeptidase.

32. Pegaptanib: is a selective vascular endothelial growth factor (VEGF) antagonist, is indicated for the treatment of neovascular (wet) age-related macular degeneration.

33. Pemetrexed is a chemotherapy drug that interferes with three folic acid related enzymes (an antifolate antineoplastic agent), is indicated, in combination with Cisplatin, for the treatment of malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

34. Perhexiline: pFOX (Fatty acid oxidase) inhibitor.

35. Raltegravir – is the first integrase inhibitor for drug resistant HIV infection.

36. Rifaximin - treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in patients 12 years old and older.

37. Sorafenib is a multikinase inhibitor targeting a number of serine/threonine and receptor tyrosine kinases, is specifically indicated for the treatment of advanced renal cell carcinoma (RCC).

38. Tezosentan: Endothelin-1-Antagonist, Cardiac remodeling inhibitor.

39. Tipranavir is a non-peptide protease inhibitor which selectively inhibits virus-specific processing of viral Gag and Gag-pol polyproteins, preventing formation of functional mature virions.

40. Ularitide: Recombinant Urodilantin, a natriuretic peptide similar to ANP, BNP.

41. Zoledronic Acid: First one yearly therapy for Osteoporosis, for Paget’s disease and post-menopausal osteoporosis.


pgmeedoubts@gmail.com

Newer Medicines 2 : 21-30

21. Lapatinib : Kinase inhibitor used in metastatic breast cancer with HER2 overexpression.

22. Lenalidomide is an orally available thalidomide analog, exerting both anti-angiogenic and immunomodulatory/anti-inflammatory properties. Thrombocytopenia and neutropenia were the most frequently observed serious adverse events.

23. Lenalidomide: An IMID – Immunomodulatory derivative of Thalidomide.

24. Levosimendan: Calcium sensitizer.

25. Maprotiline: 2nd gen. antidepressant, with predominant NA reuptake inhibitor, little anticholinergic side effects, but may produce seizures.

26. Maraviroc – the first chemokine receptor antagonist, Entry Inhibitor for drug resistant HIV infection. Maraviroc blocks the main route of virus entry into uninfected cells—chemokine receptor 5 (CCR5).

27. Mecasermin contains recombinant-DNA-engineered human insulin-like growth factor-1 (rhIGF-1). It is designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized stature growth. Patients with severe primary IGF-1 deficiency (Primary IGFD) fail to produce adequate levels of IGF-1, due to disruption of the growth hormone (GH) pathway used to promote IGF-1 release (possible GH pathway disruptions include mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects) and is specifically indicated for the long-term treatment of growth failure in pediatric patients with Primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. It is not indicated to treat Secondary IGFD resulting from GH deficiency, malnutrition, hypothyroidism or other causes; it is not a substitute for GH therapy.

28. Modafinil: for patients with narcolepsy, sleep apnea, and shift work sleep disorder.

29. Natalizumab: recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells and is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations, 300 mg IV infusion every four weeks.

30. Nesiritide: Recombinant BNP.


pgmeedoubts@gmail.com

Newer Medicines 2 : 11-20

11. Darunavir: Protease Inhibitor.

12. Dofetilide: Potassium Channel Blocker.

13. Enoximone: PDE IIIa inhibitor (Amrinone/Milrinone)

14. Eplerenone: Aldosterone antagonist.

15. Etomoxir: pFOX (Fatty acid oxidase) inhibitor.

16. Guanfacine: a selective alpha-2A-adrenoceptor agonist of CNS for ADHD.

17. HPV Vaccine (GARDASIL) against HPV 6, 11, 16 and 18.

18. Irinotecan: Topoisomerase 1 inhibitor, called CPT-11, a Camptothecin molecule, anti-leukemia agent, also useful in Colon carcinoma, producing a metabolite SN-38 which produces secretory diarrhoea manageable with Loperamide or Octreotide, and also myelosuppression especially with patients with deficient UGT1A1.

19. Istaroxime: Na+/K+ -ATPase inhibitor (E.g. Digoxin), FIRST DRUG to target LUSITROPY.

20. Ixabepilone: Microtubule inhibitor for monotherapy for metastatic breast cancer after treatment failure with other agents.

pgmeedoubts@gmail.com

Newer Medicines 1 - 10

1. Aliskiren: Renin Inhibitor

2. Ambrisentan: Endothelin receptor antagonist for treatment of pulmonary hypertension.

3. Anidulafungin: Echinocandin antifungal for treatment of candidemia, abcess, oesophagial candidasis.

4. Armodafinil : CNS stimulant, R-enantiomer of Modafinil

5. Atomoxetine: CNS noradrenaline (NA) reuptake inhibitor, first and only FDA approved non-stimulant drug for treatment of ADHD.

6. Bosentan: Endothelin-1-Antagonist, Cardiac remodeling inhibitor. Used for Rx of PPH.

7. Candoxatrilat: Inhibit Neutral Endopeptidase, increases ANP.

8. Carperitide: Recombinant BNP.

9. Cinacalcet - Cinacalcet is an oral calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. The calcium-sensing receptors on the surface of parathyroid gland cells also regulate parathyroid hormone (PTH) secretion. Increasing the sensitivity of these receptors results in lowering of PTH which subsequently lowers serum calcium levels. In addition, significant reductions in calcium may lower the threshold for seizures. Sensipar is an oral calcimimetic medication that lowers the levels of parathyroid hormone, phosphurous and calcium in patients undergoing kidney dialysis or in patients with parathroid cancer. Cinacalcet (Senipar) is indicated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients on dialysis and the treatment of elevated calcium levels (hypercalcemia) in patients with parathyroid carcinoma. The recommended starting oral dose of Sensipar is 30 mg once daily.

10. Conivaptan is a non-peptide dual arginine vasopressin (AVP) V1A and V2 receptor antagonist. It is designed to inhibit the effects of AVP, also known as antidiuretic hormone (ADH), is specifically indicated for the treatment of SIADH. . In the kidneys, AVP's activity (primarily at V2 receptors) inhibits aquaresis, or excretion of free water. By exerting antagonistic activity at both V1A and V2 receptors, the drug is designed to inhibit inappropriate/excessive AVP secretion, thereby increasing rates aquaresis. Increased water secretion is correlated with net fluid loss, increased urinary output, and decreased urinary osmolality. Can cause hypokalemia, edema, pollakuria(daytime excessive urination)


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