• Sun Pharma Recalls Nearly 500,000 Bottles of Antibiotics
• FDA Warning Letter Says Marck (Amanta) Plant Plagued by Faked Records and Dead Frogs
• A High-Potency Flu Vaccine Improves Protection in Older Adults
• Capsule Colonoscopy Can Evaluate Ulcerative Colitis in Children
• Benzodiazepines Linked to Alzheimer's Disease
• Vitamin D and Cognitive Decline
• Optimal Vitamin D Levels May Improve IVF Outcomes
• Diarrhea in the Outpatient Setting — C. difficile Is More Common Than We Thought
• Stemming Hair Loss?
Sun Pharma Recalls Nearly 500,000 Bottles of Antibiotics
According to the FDA, Caraco is recalling 454,230 cephalexin capsules in 250-mg and 500-mg doses because it wasn't following GMPs when it made the active pharmaceutical ingredients that went into them.
http://www.fiercepharmamanufacturing.com/story/sun-pharma-recalls-nearly-500000-bottles-antibiotics/2014-08-15
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MM: We rely on the FDA to do its job and discover blatant dangers to the American public and in this case they are doing just that. Many of the Indian companies that have been disciplined have had blatant violations of testing, documentation and sanitation guidelines. When the FDA sanctions companies such as compounding pharmacies that do not breach these rules, then it is merely being a bully and flexing its muscles.
FDA Warning Letter Says Marck (Amanta) Plant Plagued by Faked Records and Dead Frogs
The FDA has issued an import alert against what was Marck Biosciences sterile manufacturing plant in Kheda, India. The name has been changed to Amanta. Employees had recorded data for functions that were not performed and records, if kept at all, were often put on "scratch paper." A bathroom adjacent to the sterile line was filled with mold, and an exit loading dock was littered with dead and decaying frogs. A ceiling in the sterile manufacturing area had caved in and there were "numerous dead insects in the Sample Pass Through Room," near the sterile filling line of a parenterals facility. This ban on the Marck plant adds it to a growing list of Indian drug makers, including Ranbaxy Laboratories, Sun Pharmaceuticals, and Wockhardt, that have had plants banned for some of the same kinds of issues.
http://www.fiercepharmamanufacturing.com/story/fda-warning-letter-says-marck-plant-plagued-faked-records-and-dead-frogs/2014-08-19
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MM: High potency of typical dosing is a question that should probably not even be asked.The question that should be asked is why are we administering and even mandating a treatment that has high risk and relatively low success.
N Engl J Med 2014 Aug 14; 371:635
A High-Potency Flu Vaccine Improves Protection in Older Adults
The new preparation conferred modest benefits and little risk.
Although standard influenza vaccination is moderately helpful in protecting elders from seasonal influenza, the ongoing burden of disease in this age group mandates something better. In 2009, a high-dose inactivated vaccine preparation that contained four times the standard amount of antigen (NEJM JW Gen Med Aug 11 2009) was licensed for use in adults 65 and older on the basis of its safety and promising immunogenicity, with the caveat that clinical benefits had yet to be demonstrated. Now, researchers have provided those data in a manufacturer-supported trial conducted during the 2011–2012 and 2012–2013 flu seasons in 32,000 older adults (mean age, 73; most with ≥1 chronic medical conditions; none seriously ill) at 126 centers in the U.S. and Canada.
Flu-like illnesses were diagnosed in similar percentages of those who received standard-dose vaccinations and those who received high-dose vaccinations. However, polymerase chain reaction– or culture-confirmed influenza was significantly less common in the high-dose group (1.4% vs. 1.9%). Hospitalization rates were similar in both groups, but rates of pneumonia after respiratory illness were somewhat lower in the high-dose group; no participant died from the flu. Slightly fewer adverse events were associated with high-dose vaccination, but two high-dose recipients had vaccination-related neurological sequelae (cranial nerve palsy and acute encephalomyelitis), which were complications not seen with standard dosing.
Comment: This trial confirms that a high-potency vaccine confers somewhat more protection than standard vaccine in older adults: The investigators estimate that it increased the protection rate from 50% to 62%. Unanswered questions include the high-dose preparation's performance during flu seasons with different matches of vaccine to circulating virus (the match during the flu seasons studied was not so good) and its performance in sicker patients who are more vulnerable to flu complications.
Citation(s): DiazGranados CA et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med 2014 Aug 14; 371:635.
(http://dx.doi.org/10.1056/NEJMoa1315727)
http://www.ncbi.nlm.nih.gov/pubmed/25119609?access_num=25119609&link_
type=MED&dopt=Abstract
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MM: I tend to like approaches that are relatively non-invasive and capsule colonosopy is one of those approaches. Historically this testing procedure has not been as accurate as traditional colonoscopy but as the technology and techniques improve, hopefully the effectiveness and accuracy will improve in a similar way.
Endoscopy 2014 Jun; 46:485
Capsule Colonoscopy Can Evaluate Ulcerative Colitis in Children
In a small pilot study, diagnostic accuracy was high and no serious adverse events occurred.
In a prospective pilot study, investigators assessed the diagnostic accuracy of second-generation colon capsule endoscopy in evaluating disease activity (normal vs. active inflammation) in pediatric patients with ulcerative colitis. Colonoscopy was used as the gold-standard reference.
Thirty consecutive pediatric patients (mean age, 14.1 years) with ulcerative colitis underwent capsule study followed by colonoscopy in the late afternoon or on the following day.
One patient could not swallow a capsule. Among the other 29 patients, the sensitivity of the second-generation capsule for disease activity was 96.5%, specificity was 100%, the positive-predictive value was 100%, and the negative-predictive value was 85%. No serious adverse events occurred, and interobserver agreement was excellent (κ >0.86).
Comment: These data indicate that the colon capsule endoscopy, which may be more attractive to pediatric patients and their parents compared with conventional colonoscopy, provides good assessment of disease activity in ulcerative colitis.
Citation(s): Oliva S et al. Second-generation colon capsule endoscopy vs. colonoscopy in pediatric ulcerative colitis: A pilot study. Endoscopy 2014 Jun; 46:485. (http://dx.doi.org/10.1055/s-0034-1365413)
http://www.ncbi.nlm.nih.gov/pubmed/24777427?access_num=24777427&link_
type=MED&dopt=Abstract
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MM: It has always been quite common to give elderly patients drugs to "calm them down." This practice tends to make things easier for the caregiver but fails to address the needs or the outcome of the patient. As our population ages and more people are spending the latter portion of their lives in intermediate or skilled care living facilities, more people are losing control over their care and becoming subject to the whims of those who are supposed to watch out for their well-being. Unfortunately, many of these patients are not being "watched out for". Rather, they are being pressed into submission and that effort may be taking away from them whatever they may have left of their cognitive lives.
Benzodiazepines Linked to Alzheimer's Disease
Elderly patients that have used benzodiazepines to reduce anxiety or induce sleep are at higher risk of going on to develop Alzheimer's disease, new research finds. Using these medications places a risk of almost twice as likely to develop the disorder. The study compared benzodiazepine use in 1,796 elderly people diagnosed with Alzheimer's with that of 7,184 similar people who had no such diagnosis. Such a study design cannot by itself establish that more intensive use of the medications causes Alzheimer's disease, but it does strengthen such suspicions.
http://www.latimes.com/science/la-sci-sn-anxiety-drug-alzheimers-20140909-story.html
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MM: Vitamin D3 has a number of beneficial properties but general cognition has not been long recognized as one of these. As it is unusual for elderly or just older adults to spend much time in the sun, I strongly recommend vitamin D3 oral supplementation in the amount of 5000-10000 units daily. The bottom line is that a good target blood level of vitamin D3 should be in the 60-80ng/ml range. However, taking a supplement is simply not enough when it comes to D3. It is important to have your levels checked by a doctor or other healthcare professional.
Neurology 2014 Sep 2; 83:1
Vitamin D and Cognitive Decline
Is vitamin D deficiency in elders a risk factor for dementia and Alzheimer disease
Clear evidence supports a crucial role for vitamin D in neuronal function. Vitamin D and its metabolites mediate the synthesis of various neurotransmitters including acetylcholine, catecholamines, serotonin, and dopamine. Vitamin D also helps maintain neurite outgrowth and promote synaptic plasticity, influences neurotransmitter synthesis, protects against oxidative stress and mitochondrial dysfunction, reduces the proinflammatory response, and regulates ageing. Thus, a role for vitamin D in the pathogenesis of cognitive impairment and Alzheimer disease (AD) is plausible (Neuropathol Appl Neurobiol 2013; 39:458). To examine this association, researchers studied 1658 ambulatory adults (mean baseline age, 74) who were free from dementia, cardiovascular disease, and stroke who participated in the U.S. population-based Cardiovascular Health Study. Serum 25-hydroxyvitamin D (25[OH]D) concentrations were determined from blood samples taken in 1992 and 1993. Deficiency was defined as 25 nmol/L (10ng/ml) to <50 nmol/L (20ng/ml), severe deficiency as <25 nmol/L(10ng/ml). Follow-up for dementia and AD status was based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.
During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 with AD. The risks for both all-cause dementia and AD were significantly higher in participants who were either 25(OH)D-deficient (53% and 69% higher risks, respectively) or severely deficient (125% and 122% higher risks, respectively). Adjustments, including removal of cases diagnosed in the first year, did not alter these associations.
Comment: These results confirm that vitamin D deficiency is associated with substantially increased risks for all-cause dementia and AD. These results raise important new possibilities for treatment and prevention of these dementias.
Citation(s): Littlejohns TJ et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology 2014 Sep 2; 83:1.
(http://dx.doi.org/10.1212/WNL.0000000000000755)
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MM: This study headline only tells part of the story. Vitamin D levels below 20ng/ml demonstrated a decrease chance of successful pregnancy being achieved but those in the highest range had the greatest success in achieving pregnancy. Perhaps vitamin D3 supplementation should become a regular part of IVF protocols.
J Clin Endocrinol Metab 2014 Aug 14
Optimal Vitamin D Levels May Improve IVF Outcomes
In a prospective Italian study, women with higher serum vitamin D levels had higher pregnancy rates than those with suboptimal levels
Vitamin D plays a well-known role in mammalian reproductive function, but do vitamin D levels affect pregnancy rates in cycles involving in vitro fertilization (IVF)? Investigators at an Italian fertility center conducted a prospective cross-sectional study to assess IVF outcomes in women (age range, 18–42; body-mass index, 18–25 kg/m2; adequate ovarian reserve) with serum 25-hydroxy-vitamin-D (25[OH]D) levels <20 ng/mL compared with those having levels ≥20 ng/mL. (Levels of 20–40 ng/mL are generally considered optimal.)
Among 335 eligible participants, 154 had 25(OH)D levels <20 ng/mL and 181 had levels ≥20 ng/mL. Although similar numbers of oocytes were obtained and embryos transferred in both groups, the women with higher 25(OH)D levels had more “top-quality” embryos (based on morphologic assessment; P<0.003), relatively more of which were transferred at the blastocyst stage (P<0.07), indicating better in, vitro development. Women with higher 25(OH)D also had higher clinical pregnancy rates (31% vs. 20%; adjusted odds ratio, 2.2; 95% confidence interval, 1.2–3.8). Additional subgroup analyses indicated that women with serum 25(OH)D levels >30 ng/mL had the greatest chances of pregnancy.
Comment: This study was conducted because of prior reports suggesting that vitamin D levels might predict the likelihood of pregnancy success with IVF — but it does not establish a causal relation. Given that vitamin D is a hormone with many actions, the data are plausible; however, only a randomized, controlled trial can establish causality and confirm benefit. For now, it remains important to ensure that all of our patients have adequate vitamin D intake.
Citation(s): Paffoni A et al. Vitamin D deficiency and infertility: Insights from in vitro fertilization cycles. J Clin Endocrinol Metab 2014 Aug 14; [e-pub ahead of print].
(http://dx.doi.org/10.1210/jc.2014-1802)
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MM: C Difficile may be much more prevalent in the general community than we think. Exposure to antibiotics, pesticides and the consequent general development of intestinal dysbiosis allows this organism that is commonly found in all of our guts to become disproportionately present compared to a normal healthy gut. When this happens, then toxins may be released and the diarrhea and other GI issues may rapidly intensity. For this reason, I recommend that anyone with diarrhea take a supplement of Saccharomyces Boulardii (SB) 500mg 1-2 times daily for a period of at least 2 weeks following the resolution of the diarrhea as a means of restoring the balance of the appropriate organisms in the gut. The SB alters the acid-base balance of the gut and provides a beneficial environment for the friendly micro-organisms to thrive and battle pathogenic ones such as C. difficile.
Clin Microbiol Infect Clin Microbiol Infect 2014 Jul 7
Diarrhea in the Outpatient Setting — C. difficile Is More Common Than We Thought
An epidemiologic study in the Netherlands showed that many outpatients with CDI lack typical risk factors, and about 60% of cases go unrecognized.
Clostridium difficile infection (CDI) is a well-recognized cause of nosocomial diarrhea. Previous antibiotic treatment, older age, comorbidity, and immunocompromise are known predisposing factors. CDI also occurs in the community, but how common is it, and who is affected?
To characterize CDI among outpatients with diarrhea, researchers performed diagnostic testing — including testing for C. difficile toxin (CDT), whether or not it had been requested — on all unformed stool samples submitted by general practitioners (GPs) to three Netherlands laboratories between October 2010 and January 2012. CDT was detected — generally as the sole pathogen — in 194 (1.5%) of the 12,714 samples analyzed; Salmonella spp. were found in 198 (1.6%).Further information available for 152 of the 194 patients with CDI revealed that diarrheal symptoms had started in the community in 94%. Only 6% had developed symptoms during a stay in a long-term care facility or a hospital. Thirty-nine percent had not received antibiotics or been hospitalized before the CDI episode; 14% had no underlying diseases, previous hospitalization, or medication use.
GPs had requested CDT testing on 7% of the submitted specimens, allowing detection of 40% of the CDI cases. If the GPs had followed current Dutch recommendations to order CDT testing for all patients with diarrhea and recent hospitalization or antibiotic treatment, 18% of all samples would have been tested, allowing identification of 61% of the CDI cases.
Comment: This study suggests that many CDI episodes in the outpatient setting remain undiagnosed, partly because GPs do not recognize patients' risk factors, but also because many patients with CDI lack typical risk factors. With increasing CDI incidence in the community, this important diagnosis should be considered (and appropriate tests ordered) for all patients with diarrhea. Note to readers: At the time NEJM Journal Watch reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
Citation(s): Hensgens MPM et al. Diarrhoea in general practice: When should a Clostridium difficile infection be considered? Results of a nested case control study. Clin Microbiol Infect 2014 Jul 7; [e-pub ahead of print].
(http://dx.doi.org/10.1111/1469-0691.12758) br />
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MM: This data seems to indicate that hair re-growth may be stimulated by making the local skin healthier and improving the intrinsic communicators found in the scalp. I have to wonder if we should take a look at all the hair, scalp and skin preparations to determine which supplements will improve this intrinsic communication between scalp and hair follicles.
J Invest Dermatol 2014 Aug 15; 134:2086
Stemming Hair Loss?
Stem cell dormancy was reversed by a nearby macroenvironment of young skin.
As many of us age, the density of our scalp hair decreases. Some of us even become beautifully bald. What age-related changes contribute to hair loss? Contrary to common belief, stem cell numbers in skin do not decrease in density or number. Hair follicles maintain their stem cell compartment and normal molecular expression. However, signaling is altered, so human age-associated alopecia probably results from failure to activate stem cells in telogen hair follicles.
In a series of clever experiments, full-thickness skin with “telogen retention” (age-associated alopecia) from 24-month-old mice was transplanted onto immunodeficient 3- to 6-month-old mice. Hair cycling resumed in the transplant if the area was small. If the transplant area was large, hair cycling resumed only at the periphery. Factors from the young skin apparently diffused into the nearby transplanted skin to stimulate dormant follicles. Stem cell activation in hair follicles is regulated by periodic Wnt/β-catenin activity. In the aged mice, Wnt5a, Wnt6, β-catenin, and follistatin were activated in anagen hair follicles just as in young mice, but the stimulatory effect on stem cells was mitigated by high levels of Wnt pathway inhibitors Dkk1 and Sfrp4.
Comment: Dormant stem cells in hair follicles can be activated by Wnt and by decreased levels of Wnt pathway inhibitors. In older mice, inhibitors reside outside a stem cell's niche and keep the stem cells in a relatively dormant state (a.k.a. telogen retention). This study shows that stem cell dormancy can be reversed by the nearby macroenvironment of young skin. To reverse age-associated alopecia and age-associated skin changes (e.g., volume loss and wrinkling), the skin apparently does not need more stem cells but rather a proper balance of stimulators and inhibitors and proper binding of β-catenin to gene coactivators.
Citation(s): Chen C-C et al. Regenerative hair waves in aging mice and extra-follicular modulators follistatin, Dkk1, and Sfrp4. J Invest Dermatol 2014 Aug 15; 134:2086. (http://dx.doi.org/10.1038/jid.2014.139)
http://www.ncbi.nlm.nih.gov/pubmed/24618599?access_num=24618599&link_
type=MED&dopt=Abstract
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