Delamanid for Multidrug-Resistant Pulmonary Tuberculosis

Maria Tarcela Gler, M.D., Vija Skripconoka, M.D., Epifanio Sanchez-Garavito, M.D., Heping Xiao, M.D., Jose L. Cabrera-Rivero, M.D., Dante E. Vargas-Vasquez, M.D., Mengqiu Gao, M.D., Ph.D., Mohamed Awad, M.B., B.Ch., M.D., Seung-Kyu Park, M.D., Ph.D., Tae Sun Shim, M.D., Ph.D., Gee Young Suh, M.D., Manfred Danilovits, M.D., Hideo Ogata, M.D., Anu Kurve, M.D., Joon Chang, M.D., Ph.D., Katsuhiro Suzuki, M.D., Thelma Tupasi, M.D., Won-Jung Koh, M.D., Barbara Seaworth, M.D., Lawrence J. Geiter, Ph.D., and Charles D. Wells, M.D.

N Engl J Med 2012; 366:2151-2160June 7, 2012

BACKGROUND

Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis.

METHODS

In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months.

RESULTS

Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid.

CONCLUSIONS

Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.)

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the members of the data and safety monitoring committee — Drs. Charles Daley, Thomas Fleming, Martin Keane, and Tom Shinnick — for their close monitoring of patient safety and their expert guidance during the conduct of this trial.

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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