Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure.

Despite standard drug therapy, sympathetic nerve activity (SNA) remains high in heart failure (HF) patients making the sympathetic nervous system a primary drug target in the treatment of HF. Studies in rabbits with pacing-induced HF have demonstrated that statins reduce resting SNA, in part, due to reductions in reactive oxygen species (ROS). Whether these findings can be extended to the clinical setting of human HF remains unclear. We first performed a study in seven statin-naïve HF patients (56±2 yrs; ejection fraction 31±4%) to determine if one month of Simvastatin (40 mg/day) reduces muscle SNA (MSNA). Next, to control for possible placebo effects and determine the effect of Simvastatin on ROS, a double-blinded, placebo-controlled crossover design study was performed in six additional HF patients (51±3 yrs; ejection fraction 22±4%) and MSNA, and ROS and superoxide were measured. We tested the hypothesis that statin therapy decreases resting MSNA in HF patients and this would be associated with reductions in ROS. In Study 1, Simvastatin reduced resting MSNA (75±5 baseline vs. 65±5 statin bursts/100 heart beats, P<0.05). Likewise, in Study 2, Simvastatin also decreased resting MSNA (59±5 placebo vs. 45±6 statin bursts/100 heart beats, P<0.05). In addition, statin therapy significantly reduced total ROS and superoxide. As expected, cholesterol was reduced after Simvastatin. Collectively, these findings indicate that short-term statin therapy concomitantly reduces resting MSNA and total ROS and superoxide in HF patients. Thus, in addition to lowering cholesterol, statins may also be beneficial in reducing sympathetic overactivity and oxidative stress in HF patients.

Designer Drugs

Designer drugs (sometimes also referred to as 'club drugs') are a particular class of synthetic drugs most often associated with 'underground' youth dance parties called 'Raves', wherein participants listen to 'techno' music and experiment with psychoactive substances. These drugs have been created by changing the molecular structure of other existing drugs, to create something new with similar pharmacological effects -- hence, the name 'designer drug.' They are plentiful, cheap -- and dangerous. For example, the pharmaceutical drug fentanyl (which was originally created as an anesthetic) has been modified to be 80 to 1,000 times more potent than heroin. 

These drugs are usually prepared by underground, amateur chemists known as "cookers," designer drugs can be injected, smoked, snorted or ingested. 

Different types of designer drugs

• GHB, Super-G, Liquid-G, Liquid Ecstasy—Gama Hydroxi-Butyric Acid was originally thought to be a human growth hormone and was abuse by body builders until banned in 1991 by the FDA.  It is a clear odorless liquid with a slight salty taste which produces a alcohol-like drunken condition. Taken alone or especially when mixed with alcoholic liquor GHB produces a stupor, vomiting and comma.  It is frequently abused at clubs, parties and alcohol-free teen dance clubs and has been used as a date-rape drug. Federal law now makes it a crime for possession of GHB due to its use as a sexual assault facilitator and the many overdose deaths attributed to its use.  
• GBL, - gamma-butyrolactone, and 1,4 BD and other similar GHB relatives are being sold over the internet to avoid the growing number of laws against GHB. The human body quickly converts these chemical kissing cousins into GHB producing the same intoxicating effects but avoiding prosecution, one of the key factors driving designer drugs.
• Rohypnol—produced overseas by Hoffman-LaRoche company it is a designer analog of valium but ten times more powerful.  When mixed with alcohol it is frequently used as a "date rape" or sexual predator drug. The US Drug Enforcement Administration calls "Rophies" the "Quaalude of the '90's."  Very popular with young people in the south along with it's chemical kissing cousins Soma and Klonopin.
• Ecstasy—or MDMA a designer analog of the old 1970's drug, MDA. Ecstasy has a chemical structure that resembles meth-amphetamine, but unlike meth, can also produce mild hallucinations and a pronounced feeling of emotional closeness to other people.  Abused at Rave dance parties, long term use leads to brain damage as the cells that produce seratonin begin to die after as few of ten uses.  The most popular Designer Drug.
• Nexus or 2C-B is a phenylethylamine analog of the powerful hallucinatory drug "DOB."  It has much stronger Ecstasy-like feelings of closeness and is highly sought after for it's strong sexual enhancement properties however it produces much less powerful hallucinations then DOB.  Most pills sold as Nexus do not contain any 2C-B but rather the cheaper DXM.  True 2C-B is much more rare than MDMA at this time
• Fants-i - or 2C-i is one of the newest designer drugs responsible for several overdoses in the Chicago metropolitan area.  Sold over the internet as a research chemical, 2C-i is related to Nexus.  Fants-i is used in liquid form, has no taste or color when diluted in water, and is very dose sensitive.  Overdose produces muscle pain, nausea, intense hallucinations and panic attacks.
• EVE - or MDEA, is a closely related analog of MDMA - Ecstasy, but it is not as popular a Club Drug because it does NOT produce the feeling of emotional closeness of Ecstasy.  The EVE experience is one of being "drugged-out" or "stoned" making it a poor choice for Raves.  Police labs report 20% of Ecstasy are really knock-off drugs like EVE, PMA, or DXM.
• Double Stack - or PMA Paramethoxyamphetamine is a designer analog of meth-amphetamine first used illicitly in Australia in 1994. It is often sold as “Ecstasy” but is much more dangerous because it doesn't produce the pleasurable MDMA effects and users take more of the drug seeking the high they crave. Over dose causes a dramatic rise in body temperature in excess of 109 degrees and death occurs from hyper-thermia. Pills can be any color and often have the same head stamp as Ecstasy. Recently seen in Chicago in pill form with three diamond design, but also found widely all over the US as evidenced by news accounts in Boston and Florida.
• DXM - Dextromethorphan is very often passed off as Ecstasy at clubs and Raves, it can also be found in many over the counter cold remedies such as Robitussin DM cough syrup.  DXM produces hallucinations and a heavy "stoned" feeling in users but none of the desirable Ecstasy effects.  DXM pills are wide-spread over the United States how ever it is usually misidentified as MDMA by users and police alike.
• Special K - Ketamine is a designer analog of PCP, (Angle Dust), and is used as a powerful veterinary tranquilizer which causes hallucinations and stupor.  It is abused at Rave parties and dance clubs and has often been used as a date rape drug. It can be smoked, snorted, injected, and mixed with other drugs such as heroin. It is not active taken orally unless in very high doses.  This drug is highly addictive even though the hallucinatory effect lasts only one hour.
• Cat - Methcathanone is a designer analog of meth-amphetamine which has been brought into the country from Russia. Easy to make without the tell-tail fumes of meth-amphetamine production, cat produces a cocaine like high with hallucinations similar to mescaline.  This drug seems to be limited to the Mid-west at this time.
• Ice  - A smokable form of recrystallized meth-amphetamine with a similar effect of crack cocaine. However, unlike the crack high, which lasts only 10-15 minutes, the ice high lasts 10 hours.
• YABA - imported from southeast Asia, YABA is an ultra pure form of meth-amphetamine often combined with caffeine, and pressed into tiny pills.  The pills, small enough to fit in the end of a soda straw, can be coated, flavored, and produce a 10 hour stimulating high.
• China White - street name for Beta Hydroxide Methal Fentanyl, it is 6,000 times the potency of pure natural heroin.  There are many designer analogs of the basic narcotic fentanyl and because of their potency they have been responsible for over 2,000 narcotic overdose deaths.

EFFECTS OF USE OF DESIGNER DUGS

In general, the physical symptoms that are common among users of designer drugs include:

* Hypertension
* Increased heart rate
* Clenched teeth
* Blurred vision
* Uncontrolled tremors
* Drooling
* Anorexia
* Nausea and vomiting
* Impaired speech
* Total paralysis
* Chills and sweating
* Dehydration and heat exhaustion
* Respiratory depression
* Seizures
* Permanent brain damage
* Death

Some common psychological side effects include:

* Confusion
* Irritability
* Severe anxiety
* Extreme emotional sensitivity
* Irrational thinking
* Depression
* Amnesia
* Violent behavior
* Insomnia
* Hallucinations

DRESS Syndrome

Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.  The Drug Rash with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. It is a syndrome, caused by exposure to certain medications that may cause a rash, fever, inflammation of internal organs, lymphadenopathy, and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia, and atypical lymphocytosis. Allopurinol can cause DRESS syndrome in 2-6 weeks after allopurinol therapy.  In this text, we present a patient with complaints of fever, jaundice, dyspnea, and generalized rash after 3 months of allopurinol treatment for gout.

A 70-year-old man was admitted to another hospital with arthralgia and was diagnosed as gout; thus, he was prescribed allopurinol treatment. He was admitted to our clinic with complaints of fever, jaundice, dyspnea, and generalized rash after 3 months of allopurinol treatment for gout The patient had chronic renal failure and hypertension. There was no history of asthma or rash, nor any known allergies. Family history was unremarkable. Physical examination detected fever (38.5°C), jaundice, diffuse erythema and maculo-papular rash all over the body. Analysis of blood revealed the following: Hemoglobin, 10.1 g/dl; WBC, 19000/mm ³ ; platelet, 326000/mm ³ ; eosinophil, 7300/mm ³ ; Alanine Transaminase (ALT), 429 IU/L; Aspartate Aminotransferase (AST), 369 IU/L; Gamma-Glutamyl Transpeptidase (GGT), 481 IU/L; Alkaline Phosphatase (ALP), 773 IU/L; Lactate Dehydrogenase (LDH), 721 IU/L; urea, 76 mg/dl; creatinine, 2.1 mg/dl; uric acid, 4 mg/ dl; International Normalized Ratio (INR), 1.4; total bilirubin, 16.9 mg/dl; direct bilirubin, 8 mg/dl; and IgE, 574 IU/ ml. No immature eosinophils were observed in the peripheral blood smear. Complete urinalysis was normal. Blood and urine cultures were sterile. Hepatitis B Surface Antigen (HBsAg), IgM Antibody to Hepatitis B Core Antigen (anti-HBcIgM), Antibody to Hepatitis C Virus (anti-HCV), IgM antibody for Hepatitis A Virus (anti-HAV IgM), Anti-Cytomegalovirus IgM Antibody (anti-CMV IgM), and anti-toxoplasma IgM were negative.  Brucella  agglutination test showed negative result. Anti-Nuclear Antibodies (ANA), Anti-Mitochondria Antibody (AMA), and Anti-Smooth Muscle Antibody (SMA) were negative. Abdominal ultrasonography showed a normal liver size, grade-2 hepatosteatosis and sludge in the lumen of the gallbladder. Endoscopic Retrograde Cholangiopancreatography (ERCP) was performed to rule out mechanical icterus and was found normal. Transthoracic echocardiography showed normal left ventricular systolic function and ejection fraction was 67%. Skin biopsy was consistent with the clinical suspicion of drug-induced hypersensitivity. The case was diagnosed as DRESS syndrome. Allopurinol was stopped and steroid treatment initiated. Urea, creatinine, and liver enzymes were gradually elevated during the follow-up. Acute renal failure and acute liver failure were detected. Hemodialysis was performed for renal failure. Clinical status of the patient was gradually deteriorated. On day 24 of admission, the patient died because of DRESS.

Prevelance of hyperuricemia is 5%. Allopurinol is efficacious and safe in most patients, but intolerance is estimated to occur in up to 10% of treated patients. Severe or life-threatening allopurinol Adverse Reactions (AE) occur less frequently. 

DRESS syndrome is a severe adverse drug-induced reaction. It is a syndrome, caused by exposure to certain medications, which may cause a rash, fever, inflammation of internal organs, lymphadenopathy, and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia, and atypical lymphocytosis. DRESS is an acute, severe, and life-threatening disease, whose clinical presentation is unlike that of common drug hypersensitivity reactions. It involves multiorgan failure as a result of conditions such as nephritis, hepatitis, and encephalitis. Liver involvement and eosinophilia generally begin 2-6 weeks after the first drug is administered, that is, later than the skin reactions. Peripheral eosinophilia is a common finding in DRESS. Rash and hepatitis may persist for several weeks after the drug is discontinued and may be life-threatening. Diagnosisis based on clinical and laboratory findings.

The most common drugs known to cause DRESS syndrome are phenytoin, phenobarbital and carbamazepine. Allopurinol, sulphasalazine, nevirapine, and penicillamine are other such drugs. In a study of 38 patients with DRESS syndrome, all opurinol was found to be responsible for 5.3% of the cases. 

The pathogenesis of DRESS syndrome is not fully understood. Although the pathophysiology is still unknown, different factors have been postulated in DRESS syndrome's etiology. Immunological factors, genetic factors, and human herpes virus-type 6 are also implicated. A possible mechanism may be allopurinol or oxipurinol (major metabolite of allopurinol) hypersensitivity, and immune complex storage, which may result in vasculitis. Immunological factors, genetic factors, and Human Herpes Virus-type 6 are also implicated. 

There is no standard treatment of DRESS syndrome. The first step in treatment is discontinuation of the suspected drugs. High-dose corticosteroids can provide a dramatic improvement in clinical condition.  Early cessation of the drug implicated in the development of DRESS syndrome will result in a better outcome. The DRESS syndrome can cause life-threatening multi-organ failure.  The syndrome has a mortality rate of 10%. 

The patient in this case was admitted to our clinic with complaints of fever, jaundice, dyspnea, and generalized rash after 3 months of allopurinol treatment for gout. Leukocytosis, eosinophilia, elevation of liver enzymes, and hyperbilirubinemia were detected. Blood and urine cultures were sterile. HBsAg, anti-HBcIgM, anti-HCV, anti-HAV IgM, anti-CMV IgM, and anti-toxoplasma IgM were negative. Brucella agglutination test was negative. The ANA, AMA, and SMA were negative. ERCP was normal. Transthoracic echocardiography showed normal left ventricular systolic function and ejection fraction was 67%. The absence of immature eosinophils in the peripheral blood smear makes the diagnosis of eosinophilic leukemia unlikely. Other factors of renal failure and hepatitis (autoimmunity, infections, congestive heart failure, mechanical icterus) were ruled out. Skin biopsy was consistent with drug-induced hypersensitivity. DRESS syndrome was diagnosed with these clinical and laboratory findings. Thereafter, allopurinol treatment was stopped and steroid treatment was initiated. Urea, creatinine and liver enzymes were gradually elevated during the follow-up. Acute renal failure and transaminitis were detected. Hemodialysis was performed for the treatment of renal failure. Clinical status of the patient gradually deteriorated and on the 24^th day of admission, he died because of DRESS multipleorganfailure.

The DRESS syndrome is a severe adverse drug reaction and has high mortality rates. It warrants initiation of an early treatment. Drug use must be investigated in patients with complaints of fever, jaundice, generalized rash, acute renal failure, and acute liver failure in order to rule out the possibility of DRESS syndrome. Furthermore, judicious use of allopurinol may decrease the incidence and morbidity caused by this syndrome.

special drug delivery system

SPECIAL DRUG DELIVERY SYSTEM

Ocuserts – Thin elliptical microunits  e.g  pilocarpine ocuserts

Progetagerts – I/U contraceptive device

Transdermal patch  e.g  hyoscine, GTN,  fentanyl, nicotine

Prodrug  -  e.g levodopa

Liposomes

ž  Small artificial vesicles of spherical shape that can be produced from natural nontoxic phospholipids  & cholesterol.

ž  Because of their small size, hydrophilic & hydrophobic character as well as biocompatibility,

                                --promising  system for drug delivery.

Based on their size and number of bilayers.   

•       Small unilamellar vesicles

•       Large unilamellar vesicles

•       Multilamellar vesicles

                Bilayer component determine the rigidity and charge of bilayer.

      Depending on charge there are two types  of

         liposomes, cationic and anionic liposomes

Lipid formulations of AMB have been  produced

•       Liposomal amphotericin B -- consist of 10% AMB incorporated in uniform sized (60-80nm) unilammelar liposomes made up of lecithin

•       Liposome mediated cytotoxic drug delivery e.g.doxorubicin, cisplatin

•       Gene delivery for CFTR in cystic fibrosis.

ž  polymeric  nanoparticles

•       Biodegradable polymers

•       Because of their small size, can penetrate through smaller capillaries can be taken up by cells,   which allow efficient drug accumulation at the target sites.

•       Nanocapsules could perform like miniature man- made viruses, but they will release a pharmaceutical within the target cell, instead of delivering nucleic acid upon penetration of the cell membrane

Computerised minature pump – e.g   insulin,GnRH

Monoclonal antibody as drug carriers–   trastuzumab, rituximab

Zydus  -- mouth desolving tablet – e.g antiemetic drug

GENE THERAPY

                Introduction of functional genetic material into target cells to replace or supplement  defective genes, or to modify target cells so as to achieve therapeutic goals

Smoking vaccine fails clinical trials, $4.1 million in taxpayer dollars down the drain

An experimental new anti-smoking vaccine has failed miserably in clinical trials, faring no better than a placebo shot at helping people to quit smoking.

Produced in partnership with drug giant GlaxoSmithKline (GSK), Nabi Biopharmaceuticals' NicVAX was intended to help people quit smoking by triggering the production of antibodies that would attach to nicotine and prevent the substance from reaching the brain -- but the vaccine has proven to be nothing but non helpful medicine.

According to reports, the yearlong study involved 1,000 people that were given either NicVAX or a placebo shot, and who were tracked to observe smoking habits following treatment. Roughly 11 percent of patients who received the NicVAX shot quit smoking, but the same amount from the placebo group also quit smoking -- in other words, there was no difference at all in quit rates between the two groups.

Upon news of the failed Phase III trial, Nabi's stock price dropped a massive 70 percent, and GSK's dropped about one percent. But what is even more shocking is the fact that Nabi had used $4.1 million in taxpayer dollars to fund research for NicVAX. The company's website openly discloses that the US National Institute on Drug Abuse (NIDA) had granted $4.1 million in funding to the company back in 2005 for the project.

Remember, both Nabi and GSK are private, for-profit drug companies, and GSK had a net income in 2010 of nearly $3 billion. And yet the US government decided to take Americans' hard earned money and funnel it into a failed project that, if eventually "successful" (at least in terms of somehow gaining FDA approval, not in terms of actually working to "cure" smoking), will translate into $500 million in profits for Nabi, and possibly even more for GSK.

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How job seekers can overcome phone interviews easily??

Phone interviews are becoming a common way for employers to screen potential employees during the hiring process. Unlike traditional, in-person job interviews, phone interviews are usually fairly short, require less preparation, and can even be outsourced by the employer if necessary. These features make phone interviewing an effective way to narrow down the list of candidates before scheduling in-person interviews. Unfortunately, many people are not comfortable conducting a conversation of that importance over the phone. If the prospect of a phone interview makes you nervous, these tips can help turn an awkward interview into a confidence-inspiring success.

Preparation is the Name of the Game
When preparing for a phone interview, don’t forget that not all recruiters and employers schedule them ahead of time. At any moment, a recruiter could stumble across your resume or an employer could decide to call you in regards to a recent application. Your chances for success in your job search will be greatly improved if you try to always expect the unexpected (especiallyduring a job interview).

Keep Your Resume Near the Phone
Knowing that you could get a call from a recruiter or an employer at any moment, you should always keep a recent copy of your resume near the phone. That way, whether or not your phone interview is anticipated, you will have all the information you need right at your fingertips. Of course for a job interview, your resume is not the only resource you should keep handy.

Create a log for keeping track of the resumes you send out, recording each company, position title, contact name, date the position was applied for, and qualifications for the job. If you have a chance to research the company, make a file with that information, and keep it near the phone as well. Finally, you should always have access to a notepad and pen during a phone interview, so that you can write down the interviewer’s name, key questions he or she asked, and your responses.

Practice (and a Cheat Sheet) Makes Perfect
Just like with a traditional job interview, you should try to anticipate questions the interviewer might ask. If you have come up with examples and practiced your answers ahead of time, you will sound much more intelligent and confident in the interview. Moreover, since the interviewer cannot see you, there is nothing to stop you from referring to a “cheat sheet” – notes to help you remember your practiced answers, so that you never sound like you have been taken off guard.

When you practice your answers and put together your cheat sheet, you should think about job interview questions that are traditionally asked, such as:

• Tell me about yourself.
• What are your strengths and weaknesses?
• Where do you see yourself in 1/5/10 years?
• What is your leadership style? Please give an example of a real situation.
• Describe a situation where you had to work with others to solve a problem.
• Give me an example of a stressful situation you have encountered on the job. How did you handle it?
• Tell me about your three greatest accomplishments in your career.
• Do you have any questions?

Many of these questions are difficult to answer on the spot. By preparing your answers ahead of time, you give yourself the opportunity to think through your answers carefully. Your notes will refresh your memory if you draw a blank, and help prevent you from freezing up during the interview.

Giving a Fabulous Phone Interview
If you’ve done your homework, the phone interview itself should be a breeze. The important thing at this point is to remember to make sure the interviewer can hear and understand you – and vice versa – as well as possible. During the phone interview, you should:

• Find a quiet place. Children, pets, televisions, and radios are all noisy distractions that should be avoided. If the phone interview is scheduled in advance, you can arrange to have a quiet room all to yourself. If you receive the phone call unexpectedly, retreat into a quiet room or suggest another time for the interview.

• Sip water periodically. Nervousness often causes your mouth to dry out, which can in turn change the way your voice and pronunciation sounds to the interviewer. If you know about the phone interview ahead of time, you can have a glass of water on hand, along with the other materials you have prepared.

• Avoid eating, smoking, or chewing gum. Excess movement of your mouth and throat will make you harder to understand, and possibly distract or even irritate the interviewer.

• Give short answers. Many people talk too much when they are nervous. This is especially easy to do in a phone interview, because you don’t have the other person’s visual cues to indicate when it’s their turn to talk. To make sure you don’t make this mistake, only talk long enough to answer the question. A moment of silence, while it might seem awkward to you, lets the interviewer know that you are done.

Speak slowly and clearly. Speaking too fast, whether out of nervousness or habit, will hurt your chances by making you harder to understand. Instead, make a conscious effort to slow down and enunciate clearly.

• Stand, stretch, or pace occasionally. Standing improves the quality of your voice by increasing airflow to your lungs. Additionally, many people find it easier to adopt a salesperson-like attitude when they are standing or moving around. As a result, changing your posture occasionally can make you sound more confident to the interviewer.

• Smile. Believe it or not, a smile changes the quality of your voice. If you are smiling, the interviewer will hear it in your tone!

Finishing Your Phone Interview on the Right Foot

The phone interview is drawing to a close; what do you do now? These final moments are just as important as the preparation and the interview itself, as they can determine what comes next.

• Thank the interviewer. Verbally thank the interviewer for taking the time to speak with you. If you don’t remember his or her name, ask for it again and write it down, so that you can send a thank-you note as well.

• Suggest an in-person interview. The whole point of the phone interview was to score a traditional job interview, so if the interviewer doesn’t mention what will happen next, you should bring it up. For example, you can say, “Thank you very much for taking the time to call me. I’d like to have the opportunity to meet in person. When will you be scheduling the next round of interviews?”

• Reiterate your interest in the position. You want to leave the interviewer with the impression that you are enthusiastic about the job. Let him or her know how excited you are about the prospect of working with the company.

• Send a thank-you note. Just as with a traditional job interview, you should follow up with a polite thank-you note. You can also use the thank-you note to reiterate your interest in scheduling an in-person interview. Just be sure to send the thank-you note out promptly, as the interviewer may soon be making final decisions about who to call back!

Many people find a phone interview more nerve-wracking than a traditional job interview. This doesn’t have to be the case, however. While some phone interviews happen with little or no warning, in most cases you have just as much time to prepare as you would ordinarily, with the added benefit of being able to use your notes during the interview.