Investigative IL-6 Inhibitor Sirukumab Reduces Symptoms in Patients With Rheumatoid Arthritis

LONDON -- May 31, 2011 -- Rheumatoid arthritis patients failing to respond to the disease-modifying agent methotrexate appear to achieve a reduction in symptoms when treated with the investigational interleukin-6 inhibitor sirukumab, researchers said here at the 2011 Annual Meeting of the European League Against Rheumatism (EULAR).

“Not all patients respond to initial treatment, and in my experience a proportion of patients receiving currently available therapies will either have an inadequate response or lose response over time,” said Josef Smolen, MD, Medical University of Vienna, Vienna, Austria.

“There continues to be a need for additional therapeutic options for the treatment of rheumatoid arthritis -- a serious, progressive autoimmune disease. The results we have seen to date with sirukumab are promising, and we look forward to seeing future data from the ongoing clinical studies,” he said.

Results from the phase 2 multicentre, randomised, double-blind, dose-finding study showed that patients treated with sirukumab achieved a significantly greater reduction in Disease Activity Score 28 (DAS28 CRP) at week 12, the primary endpoint of the study, researchers reported on May 27.

At week 12, in this proof-of-concept trial, the 19 patients on methotrexate plus placebo achieved a score reduction 0.65 while the 17 patients on methotrexate and sirukumab showed a reduction of 1.66 (P =.001).

All patients remained on their background medication of methotrexate and were randomised to receive subcutaneous injections of sirukumab 100 mg or placebo once every 2 weeks from week 0 to week 10. At week 12, an interim analysis showed that 82% of patients in the sirukumab group achieved good or moderate DAS28 C-reactive protein (CRP) response compared with 32% of patients receiving placebo plus methotrexate (P =.015).

By week 12, at least a 20% improvement in American College of Rheumatology scores (ACR20) was seen in 75% of sirukumab-treated patients compared with 21% of patients receiving placebo plus methotrexate patients (P =.002).

Treatment with sirukumab was generally well tolerated through 10 weeks of treatment. Three patients discontinued the study before week 12 due to an adverse event -- one being a serious case of staphylococcal cellulitis. The infection resolved. Another patient was withdrawn after developing pneumonia and the third patient -- in the placebo group -- quit the study due to worsening rheumatoid arthritis. No deaths, cardiovascular events, or gastrointestinal perforations were reported.

The study was funded by Centocor Ortho Biotech Inc.

By Alex Morrisson
Presented at EULAR

[Presentation title: Proof-of-Concept for CNTO 136, a Human Anti-Interleukin-6 Monoclonal Antibody, in a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy. Abstract FRI0345]

Cancer drug can reverse heart failure

A promising cancer drug can reverse a heart failure resulting from high blood pressure (BP).

The drug, a type of histone deacetylase (HDAC) inhibitor being evaluated in ongoing clinical trials, has been shown to reverse the harmful effects of autophagy in heart muscle cells of mice, according to a recent study.

Autophagy is a natural process by which cells eat their own proteins to provide needed resources in times of stress, the journal Proceedings of the National Academy of Sciences reports.

"This opens the way for a new therapeutic strategy in hypertensive (BP related) heart disease, one we can test for potential to promote regression of heart disease," said Joseph Hill, chief of cardiology at the University of Texas Southwestern Medical Centre, who led the study.

Hill, senior study author, and other researchers have shown previously that all forms of heart disease involve either too much or too little autophagy, according to a Texas statement.

For example, in the presence of high BP, the heart enlarges, or hypertrophies and autophagy is turned on. Ultimately, the hypertension-stressed heart can go into failure.

Prior research from Hill's laboratory has shown that HDAC inhibitors blunt disease-associated heart growth, so researchers designed this study to determine what impact a particular type of HDAC inhibitor had on autophagy.

The researchers engineered mice with overactive autophagy and induced hypertrophy leading to heart failure. Scientists then gave the mice an HDAC inhibitor known to limit autophagy.

"The heart decreased back to near its normal size, and heart function that had previously been declining went back to normal," Hill said. "That is a powerful observation where disease regression, not just disease prevention, was seen." 

Source :  Research brain tumour : www.anticancer.de/astrocytoma-study - Phase III study for anaplastic astrocytoma accepts patients.

Thank you All !!!

Killing a Pregnant Lady for Having a Baby Girl is INSANE !! Giving birth to a Baby Girl is not in Her Hand !!

Recently, This incident happened in Andhra Pradesh, INDIA.. 

Now a Dayz.... In this New Modern World too....there are many instances happening all around like this !!

A Husband killed his Pregnant Wife for Having a Baby Girl..

Although, Scanning is Prohibited and Illegal in INDIA, He has Done Scanning to his Wife, to confirm whether He will be having a BABY girl/ Baby Boy..

A Scanning Centre & A Doctor for Money... Done Scanning and Revealed the reports that He is going to have a BABY GIRL..

Husband who already had two daughters by his WIFE, has lost his patience, Killed his WIFE that She is the REASON for this Whole thing.

Let me Clear to you all that Birth of a BABY is completely dependent on the Husband !!

The chromosomes of a Man --- X, Y

The Chromosomes of a Woman ---  X, X

So, by the above picture,, you can clearly understand that Only MAN is Responsible for the BIRTH of a BABY .. no matter whether it may be a Girl or a Boy !!

Vancomycin mechanism of action: an animation

Vancomycin is a tricyclic glycopeptide that has gained clinical importance thanks to its effectiveness against organisms such as MRSA and enterococci. It has activity against Gram-positive rods and cocci, Gram-negative rods are resistant to its bactericidal action.

Some clinical uses of IV vancomycin include treatment of infective endocarditis and sepsis caused by MRSA. Since vancomycin is poorly absorbed,  it is used only in treatment of enterocolitis caused by C. difficile.

Vancomycin adverse effects include skin flushing (red-man syndrome), fever, chills and phlebitis at the infusion site. Ototoxicity and nephrotoxicity must be kept in mind when treating patients that are receiving other drugs.

As you can see in the animation below, vancomycin binds to the pentapeptides of the peptidoglycan monomers and prevents the transglycosylation step in peptidoglycan polymerization. This weakens the cell wall and damages the underlying cell membrane.

Mechanism of action

About the animation author

Dr. Gary Kaiser is a Professor of Microbiology at The Community College of Baltimore County, Catonsville Campus located in Baltimore, Maryland.

Make sure you visit his excellent microbiology website: The Grapes of Staph.

References


Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.


Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Gilbert, D; Moellering R (editors) “Sanford Guide to Antimicrobial Therapy”, 39th edition. Antimicrobial therapy: 2009

Hauser, A. “Antibiotic Basics for Clinicians: Choosing the Right Antibacterial Agent”.1st edition. LWW:2007

Gallagher, J. “Antibiotics Simplified”. 1st edition. Jones & Bartlett Publishers: 2008

Botulinum toxin type A (Botox) mechanism of action

Botox mechanism of action

The presynaptic neuromuscular nerve ending contains vesicles prepared to release the neurotransmitter acetylcholine. Neuronal stimulation initiates a cascade of events that leads to the fusion of the neurotransmitter containing vesicle with the nerve membrane. This process is facilitated by a group of proteins comprising the SNARE complex. The membrane fusion results in the release of acetylcholine into the synaptic cleft by a process of exocytosis.




Acetylcholine diffuses and eventually binds to acetylcholine receptors in the muscle, leading to muscle contraction.
Botox (botulinum toxin type A) consists of a heavy chain of 100 kDa and a light chain of 50 kDa making up the 150 kDa core type A molecule. The toxin is protected by accessory hemaglutinin and non-toxic non- hemaglutinin proteins.
This illustration shows a cross section of the spine, with a motor neuron extending into the muscle and a sensory neuron extending out of the muscle. After injection of Botox it would be expected that most of the neurotoxin would remain in the injection site. The Botox core molecule dissociates from the accessory proteins and targets the nerve endings. The binding domain of the Botox core molecule is the C-terminal portion of the heavy chain.
The Botox core molecule enters the nerve cell by a process of receptor mediated endocytosis. It is the heavy chain that contains the binding domain. The toxin is now contained in a membranous vesicle inside the cell. Soon after, the light chain is released into the cytoplasm of nerve terminal, where it begins to cleave one of the SNARE proteins.


In motor neurons, the light chain of the Botox core molecule blocks the release of acetylcholine by cleaving SNAP-25, which is an essential component of the SNARE complex. When acetylcholine cannot be released, muscle contraction cannot occur. In sensory neurons, the light chain is believed to cleave SNAP-25 by a similar mechanism, thereby blocking the release of neuropeptide neurotransmitters and inhibiting the desensitation of pain nerves.
The toxin does not appear to affect the conduction along the nerve fiber or the synthesis or storage of acetylcholine.

Renal physiology and diuretics mechanism of action.

Mechanism of action of loop diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

These drugs inhibit NKCC2, the luminal Na⁺/K⁺/2Cl^- transporter in the thick ascending limb of Henle’s loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K⁺ recycling (Figure 15-3). This positive potential normally drives divalent cation reabsorption in the loop (Figure 15-3), and by reducing this potential, loop diuretics cause an increase in Mg²⁺ and Ca²⁺ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D-induced intestinal absorption of Ca²⁺ can be increased and Ca²⁺ is actively reabsorbed in the DCT, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia, Ca²⁺ excretion can be usefully enhanced by treatment with loop diuretics combined with saline infusions.

Loop diuretics induce synthesis of renal prostaglandins, which participate in the renal actions of these diuretics. NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis.

In addition to their diuretic activity, loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs, and in anephric patients.

Mechanism of action of tiazide diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na⁺/Cl^- transporter (NCC). In contrast to the situation in the TAL, where loop diuretics inhibit Ca²⁺ reabsorption, thiazides actually enhance Ca²⁺ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na⁺ and passive Ca²⁺ reabsorption. In the DCT, lowering of intracellular Na⁺ by thiazide-induced blockade of Na⁺ entry enhances Na⁺/Ca²⁺ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca²⁺. While thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria.

The action of thiazides depends in part on renal prostaglandin production. As described above for the loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions.

Mechanism of action of potasium sparing diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

Potassium-sparing diuretics reduce Na⁺ absorption in the collecting tubules and ducts. Na⁺ absorption (and K⁺ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H⁺ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists (Table 15-2).

Spironolactone and eplerenone bind to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone. Amiloride and triamterene do not block the aldosterone receptor but instead directly interfere with Na⁺ entry through the epithelial sodium ion channels (ENaC) in the apical membrane of the collecting tubule. Since K⁺ secretion is coupled with Na⁺ entry in this segment, these agents are also effective potassium-sparing diuretics.

The actions of the aldosterone antagonists depend on renal prostaglandin production. As described above for loop diuretics and thiazides, the actions of K⁺-sparing diuretics can be inhibited by NSAIDs under certain conditions.

Mechanism of action of osmotic diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na⁺ as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia.

P-glycoprotein: animation showing its role in chemotherapy resistance

Some introductory information about MDR1, the protein that mediates resistance to chemotherapeutic agents, from Wikipedia:

P-glycoprotein (plasma gycoprotein, abbreviated as P-gp or Pgp) is a well-characterized ABC-transporter of the MDR/TAP subfamily. P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1. P-glycoprotein has also recently been designated CD243 (cluster of differentiation 243). In humans, P-glycoprotein is encoded by the ABCB1 gene.
Pgp is extensively distributed and expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, and capillary endothelial cells comprising the blood-brain barrier.

The animation below, produced by CancerQuest, shows how the MDR protein ejects drugs once they have entered the cell.

G protein-coupled receptors: Description & 3-D video

G protein-coupled receptors are the most abundant class of receptors in the human body. These receptors are exposed at the extracellular surface of the cell membrane, traverse the membrane, and possess intracellular regions that activate a unique class of signaling molecules called G proteins. (G proteins are so named because they bind the guanine nucleotides GTP and GDP.) G protein-coupled signaling mechanisms are involved in many important processes, including vision, olfaction, and neurotransmission.

G protein-coupled receptors all have seven transmembrane regions within a single polypeptide chain. Each transmembrane region consists of a single α helix, and the α helices are arranged in a characteristic structural motif that is similar in all members of this receptor class. The extracellular domain of this class of proteins usually contains the ligand-binding region, although some G protein-coupled receptors bind ligands within the transmembrane domain of the receptor. In the resting (unstimulated) state, the cytoplasmic domain of the receptor is noncovalently linked to a G protein that consists of α and βγ subunits. Upon activation, the α subunit exchanges GDP for GTP. The α-GTP subunit then dissociates from the βγ subunit, and the α or βγ subunit diffuses along the inner leaflet of the plasma membrane to interact with a number of different effectors.

These effectors include adenylyl cyclase, phospholipase C, various ion channels, and other classes of proteins. Signals mediated by G proteins are usually terminated by the hydrolysis of GTP to GDP, which is catalyzed by the inherent GTPase activity of the α subunit .

One major role of the G proteins is to activate the production of second messengers, that is, signaling molecules that convey the input provided by the first messenger—usually an endogenous ligand or an exogenous drug—to cytoplasmic effectors . The activation of cyclases, such as adenylyl cyclase, which catalyzes the production of the second messenger cyclic adenosine-3′,5′-monophosphate (cAMP), and guanylyl cyclase, which catalyzes the production of cyclic guanosine-3′,5′-monophosphate (cGMP), constitutes the most common pathway linked to G proteins. In addition, G proteins can activate the enzyme phospholipase C (PLC) which, among other functions, plays a key role in regulating the concentration of intracellular calcium. Upon activation by a G protein, PLC cleaves the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to the second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). IP3 triggers the release of Ca2+ from intracellular stores, thereby dramatically increasing the cytosolic Ca2+ concentration and activating downstream molecular and cellular events. DAG activates protein kinase C, which then mediates other molecular and cellular events, including smooth muscle contraction and transmembrane ion transport. All of these events are dynamically regulated, so that the different steps in the pathways are activated and inactivated with characteristic kinetics.

A large number of Gα protein isoforms have now been identified, each of which has unique effects on its targets. A few of these G proteins include G-stimulatory (Gs), G-inhibitory (Gi), Gq, Go, and G12/13. Examples of the effects of these isoforms are shown in Table 1-4. The differential functioning of these G proteins, some of which may couple in different ways to the same receptor in different cell types, is likely to be important for the potential selectivity of future drugs. The βγ subunits of G proteins can also act as second messenger molecules, although their actions are not as thoroughly characterized.

One important class in the G protein-coupled receptor family is the β-adrenergic receptor group. The most thoroughly studied of these receptors have been designated β1, β2, and β3. As discussed in more detail in Chapter 9, Adrenergic Pharmacology, β1 receptors play a role in controlling heart rate; β2 receptors are involved in the relaxation of smooth muscle; and β3 receptors play a role in the mobilization of energy by fat cells. Each of these receptors is stimulated by the binding of endogenous catecholamines, such as epinephrine and norepinephrine, to the extracellular domain of the receptor. Epinephrine binding induces a conformational change in the receptor, activating G proteins associated with the cytoplasmic domain of the receptor. The activated (GTP-bound) form of the G protein activates adenylyl cyclase, resulting in increased intracellular cAMP levels and downstream cellular effects.

Source of text: David Golan: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition

Mechanism of ionotropic receptors or ligand-gated ion channels (LGICs)

In pharmacology, receptors can be divided into 4 general groups:
1. Ion channels:

• Ligand gatedace

• Voltage gated

• Second messenger regulated

2. G protein coupled receptors
3. Receptor tyrosine kinase
4. Intracellular hormone receptors: like  the glucocorticoid receptor

The video animation below shows the activation of a ionotropic receptor or ligand-gated ion channel (LGIC):

An excerpt on the topic from Katzung’s textbook:

Ligand-Gated Channels
Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands include acetylcholine, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters.
Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane. For example, acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor (AChR), which allows Na⁺ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential-a depolarization.

Mechanisms that Bacteria Use to develop antibiotic resistance

Mechanisms of Antimicrobial Resistance

Mutation

Destruction or Inactivation

Efflux ( 1:00)

Genetic Transfer

Conjugation

Transformation

Transduction

Cisplatin and its Mechanism of Action

Mechanism of Action.

Cisplatin, carboplatin, and oxaliplatin enter cells by diffusion, and by an active Cu2+ transporter (Kruh, 2003). Inside the cell, the chloride atoms of cisplatin may be displaced and the compound may be inactivated directly by reaction with nucleophiles such as thiols. Chloride is replaced by water, yielding a positively charged molecule. In the primary cytotoxic reaction, the aquated species of the drug then reacts with nucleophilic sites on DNA and proteins. Aquation is favored at the low concentrations of chloride inside the cell and in the urine. High concentrations of chloride stabilize the drug, explaining the effectiveness of chloride diuresis in preventing nephrotoxicity (see below). Hydrolysis of carboplatin removes the bidentate cyclobutanedicarboxylato group; this activation reaction occurs slowly.

The platinum complexes can react with DNA, forming both intrastrand and interstrand cross-links. The N7 of guanine is a particularly reactive site, leading to platinum cross-links between adjacent guanines on the same DNA strand; guanine-adenine cross-links also readily form and may be critical to cytotoxicity (Parker et al., 1991). The formation of interstrand cross-links is less favored. DNA adducts formed by cisplatin inhibit DNA replication and transcription and lead to breaks and miscoding, and if recognized by p53 and other checkpoint proteins, induction of apoptosis. Although no conclusive association between platinum-DNA adduct formation and efficacy has been documented, the ability of patients to form and sustain platinum adducts appears to be an important predictor of clinical response (Reed et al., 1986). Preclinical data suggest that the formation of the platinum-adenosine-to-guanosine adduct may be the most critical adduct in terms of cytotoxicity.

The specificity of cisplatin with regard to phase of the cell cycle appears to differ among cell types, although the effects of cross-linking are most pronounced during the S phase. Cisplatin is mutagenic, teratogenic, and carcinogenic. The use of cisplatin- or carboplatin-based chemotherapy for women with ovarian cancer is associated with a fourfold increased risk of developing secondary leukemia (Travis et al., 1999).

Source:Goodman And Gilman’s The Pharmacological Basis of Therapeutics

Happy Mothers Day !! Mothers --- We Salute You !!!

Happy Married Life !!