Federal Drug Agency Research Articles

7296 Gestational Diabetes RT-Continuous Glucose Monitoring Users Utilized Fingerstick less in Pregnancy than Recommended Compared to Fingerstick Monitoring Alone with No Difference in A1c Outcomes

Abstract Disclosure: N.M. Ehrhardt: Advisory Board Member; Self; Bayer, Inc., Novo Nordisk, Dexcom. Grant Recipient; Self; Novo Nordisk. Research Investigator; Self; Novo Nordisk, Dexcom. P. Mandava: None. E. Fay: None. G. Abdalla: None. S. Fonda: None. Background: The Federal Drug Agency recently approved continuous glucose monitoring (CGM) use in gestational diabetes (GDM). However, self-monitoring of blood glucose (SMBG) with fingersticks is still recommended as an adjunct to CGM use. Here we report on SMBG with and without CGM and A1c, as part of a randomized controlled trial (RCT) of CGM for women with GDM. Methods: This is an RCT of 104 participants with GDM who were randomized to real-time CGM (RT-CGM) (N=48) or SMBG alone (control group; N=56). Sixty-one percent in the control group (N=34) withdrew after randomization because they desired a CGM device. Data collection was completed remotely given COVID-19 pandemic. A1c data was collected at baseline and 36 weeks gestation. Fingerstick data was collected at each of 4 study visits (2 weeks apart) until 38 weeks or delivery. All participants were advised to perform SMBG by fingerstick as instructed by their obstetric provider. This analysis is of participants who completed the study (control N=22; RT-CGM N=47). Results: The average age was 33.77 (+/- 5.26) years, 68.11% had a college degree or greater, 69.57% had an income of >$50,000, 95.65% had health insurance, 30.43% reported being Asian and 42.03% reported being white. Baseline mean A1c (+/- SD) was 5.39 (+/- 0.39) in the RT-CGM group and 5.41 (+/- 0.37) in in the control group. Mean A1c at ∼36 weeks of pregnancy was 5.44 (+/-0.43) in the RT-CGM group and 5.37 (+/- 0.44) in the control group. In the RT-CGM group, 20/47 (42.55%) provided SMBG data for ≥3 study visits, 18/47 (38.30%) had data for 1-2 visits, and 9/47 (19.15%) provided no SMBG data at all 4 visits. The mean (+/- SD) tests/day for the RT-CGM group who provided any meter data was 1.31 (+/- 1.89). In the control group, 16/22 (72.73%) provided SMBG data for ≥3 visits, 2/22 (9.09%) had data for 1-2 visits, and 4/22 (18.18%) never provided SMBG data. The mean (+/- SD) tests/day for the control group was 3.4 (+/- 0.73). For the RT-CGM group, simple correlation analyses found no association between number of visits in which fingerstick data were provided and A1c at visit 3 (r=-0.14; p=0.40) or average fingerstick tests/day and A1c at visit 3 (r=0.10; p=0.40). For the control group, there was no association between number of study visits in which fingerstick data were provided and A1c at visit 3 (r=0.38; p=0.11). However, for the control group, more fingerstick tests/day was associated with lower A1c at visit 3 (r=-0.45; p=0.07). Conclusions. Data is limited by missing data as participants did not always supply fingerstick data. Overall A1c in both groups remained stable, despite less SMBG testing in the CGM group. This suggests that SMBG data may add little in GDM management in conjunction with CGM use. More data is necessary to remove the recommended requirement for fingerstick with CGM in pregnancy. Presentation: 6/2/2024

Metformin toxicity in the intensive care unit: A case series and review of the literature.

Metformin toxicity is a life-threatening condition with high morbidity and mortality. Toxicity predominantly occurs in the setting of acute renal dysfunction, as the drug is solely eliminated by the kidneys. While this risk is widely known to clinicians, diagnosing metformin toxicity is challenging because commercially available serum metformin levels require days to weeks to result. Therefore, the intensivist must rely on medical history, clinical presentation, and routine laboratory findings to make the preliminary diagnosis. Treatment of metformin toxicity includes supportive fluid hydration, vasopressors, and emergent hemodialysis (HD). We report three critically ill patients who had near-fatal severe metformin-induced lactic acidosis. Their metformin levels were markedly higher than the toxicity threshold reported by the Federal Drug Agency. These patients made a prompt and complete recovery after the initiation of HD. We also review the pathophysiology, clinical presentation, diagnosis, and treatment of metformin toxicity.

Efficient stereoselective hydroxylation of deoxycholic acid by the robust whole-cell cytochrome P450 CYP107D1 biocatalyst

Deoxycholic acid (DCA) has been authorized by the Federal Drug Agency for cosmetic reduction of redundant submental fat. The hydroxylated product (6β-OH DCA) was developed to improve the solubility and pharmaceutic properties of DCA for further applications. Herein, a combinatorial catalytic strategy was applied to construct a powerful Cytochrome P450 biocatalyst (CYP107D1, OleP) to convert DCA to 6β-OH DCA. Firstly, the weak expression of OleP was significantly improved using pRSFDuet-1 plasmid in the E. coli C41 (DE3) strain. Next, the supply of heme was enhanced by the moderate overexpression of crucial genes in the heme biosynthetic pathway. In addition, a new biosensor was developed to select the appropriate redox partner. Furthermore, a cost-effective whole-cell catalytic system was constructed, resulting in the highest reported conversion rate of 6β-OH DCA (from 4.8% to 99.1%). The combinatorial catalytic strategies applied in this study provide an efficient method to synthesize high-value-added hydroxylated compounds by P450s.

Comprehensive UHPLC–MS screening methods for the analysis of triazolopyrazine precursor and its genotoxic nitroso-derivative in sitagliptin pharmaceutical formulation

A case study on Sitagliptin drug products and Sitagliptin/Metformin drug products concerning contamination with N-nitrosamines was performed using two newly developed analytical methods for determination of N-nitroso-triazolopyrazine (NTTP; 7-nitroso-3-(trifluoromethyl)–5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine) and its precursor triazolopyrazine (3-(trifluoromethyl)–5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine). The method for determination of triazolopyrazine was previously unpublished, the method for determination of NTTP was published only for analysis of active pharmaceutical ingredient Sitagliptin and not the drug forms. Solving the N-nitrosamine contamination is requested by regulatory authorities all over the world and thus is vital for all pharmaceutical companies. The solution always requires a sensitive analytical method. Both newly developed methods use liquid chromatography coupled with mass spectrometry (single quadrupole analyzer in case of triazolopyrazine and triple quadrupole analyzer in case of NTTP). Separation of triazolopyrazine was achieved on a column Acquity CSH C18 using a mobile phase consisting of aqueous ammonium formate buffered at pH 4.2 and acetonitrile. Detection was performed using positive electrospray and selected ion monitoring at m/z 193. Separation of NTTP was achieved on a column Acquity HSS T3 using a mobile phase consisting of 0.1 % formic acid in water and methanol. Detection was performed using positive electrospray and multiple reaction monitoring at transitions m/z 222.15→42.05 (collision energy 17 eV) and m/z 222.15→192.15 (collision energy 11 eV). Two issues specific to NTTP and triazolopyrazine previously not described in scientific literature were successfully troubleshooted. Spontaneous degradation of Sitagliptin to triazolopyrazine and methyl (R)–3-amino-4-(2,4,5-trifluorophenyl)butanoate was solved by using N,N-dimethylformamide as sample solvent during development of the method for quantitation of triazolopyrazine. A bad peak shape of NTTP due to the presence of rotamers of NTTP was successfully troubleshooted by increasing column temperature. Both methods were used during an optimization study of manufacturing of Sitagliptin and Sitagliptin/Metformin drug products. The goal of the study was to decrease NTTP content in the final drug product under the strict legislative limit set by Federal Drug Agency. The efficacy of several solutions was proven, but could not be fully disclosed due to Intellectual Property Protection policy of Zentiva. Instead, a brief review of recently published strategies to cope with N-nitrosamine contamination is presented.

Hidden Dangers: Herbal and Dietary Supplement Induced Hepatotoxicity

Herbal and dietary supplements represent a multi-billion-dollar industry reportedly used by over half of American adults. However, these products are not regulated by the Federal Drug Agency and contain a wide range of contaminants, leading to over 50,000 adverse events each year. This review aims to highlight the widespread use and current regulatory status of herbal and dietary supplements, identify the presentation and diagnostic dilemmas faced with liver injury, and discuss the most common agents implicated in herbal and dietary supplement hepatotoxicity.

Femtosecond-laser-assisted Small Incision Lenticule Extraction to Treat Refractive Error: A Narrative Review

With the approval of the Federal Drug Agency of the USA in 2018, femtosecond laser-assisted small incision lenticule extraction (SMILE) became an officially available option in several countries including Saudi Arabia to treat myopia and astigmatism. Intense marketing by industries has placed both clients and corneal surgeons into a dilemma of the plus and minuses of this option. Although several reviews compare SMILE to other conventional methods, especially laser in situ keratomileusis, this narrative review perhaps for the first time offers a detailed summary of this procedure and compares two sets of published literature, by authors from China and other countries. The efficacy and safety of SMILE seem to outnumber the complications and high cost of the investment. Its long-term usefulness for treating high myopia and hyperopia is still a matter of research.

The Effect of Biological Treatment on Fatigue in InflammatoryBowelDisease: A Systematic Review and Meta-analysis.

Fatigue is a frequent complaint in patients with inflammatory bowel disease. Biological drugs have demonstrated beneficial effects on some extraintestinal manifestations, but the effect on fatigue is not clear. This study investigated the effects of biological and small molecule drugs approved for inflammatory bowel disease on fatigue. We performed a systematic review and meta-analysis of randomized, placebo-controlled trials reporting Federal Drug Agency (FDA)-approved biological and small molecule drugs for use in ulcerative colitis and Crohn's disease in which measures of fatigue were recorded before and after treatment. Only induction studies were included. Maintenance studies were excluded. We searched Embase (Ovid), Medline (Ovid), PsycINFO (Ovid), Cinahl (EBSCOhost), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov in May 2022. Risk of bias was analyzed using the Cochrane risk-of-bias tool. Standardized mean difference was used to measure the treatment effect. A total of seven randomized controlled trials composed of 3835 patients were included in the meta-analysis. All of the studies included patients with moderately to severely active ulcerative colitis or Crohn's disease. The studies used three different generic fatigue instruments: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale versions 1 and 2. Overall treatment with biological or small molecule agents showed a beneficial effect compared with placebo, with a standardized mean difference of 0.25 (95% confidence interval 0.15-0.34, p < 0.001). The effect was independent of type of drug or subtype of inflammatory bowel disease. The risk of bias was considered to be low for all domains except for missing outcome data. Even though the included studies were of high methodological quality, the review is limited by the small number of studies included and that the available studies were not designed to evaluate fatigue specifically. Biological and small molecule drugs used in inflammatory bowel disease have a consistent, though small, beneficial effect on fatigue.

Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression.

Psychotic treatment-resistant depression is a complex and challenging manifestation of mood disorders in the clinical setting. Psychotic depression is a subtype of major depressive disorder characterized by mood-consistent hallucinations and/or delusions. Psychotic depression is often underdiagnosed and undertreated. Ketamine appears to have rapid and potent antidepressant effects in clinical studies, and the Federal Drug Agency approved the use of ketamine enantiomer esketamine-nasal spray for treatment-resistant depression pharmacotherapy in 2019. This study aimed to assess the usage of ketamine for major depressive disorder with psychotic features as an add-on treatment to the standard of care. Here we present four inpatients suffering from treatment-resistant depression with psychotic features, including one with severe suicidal crisis, all treated with 0.5 mg/kg intravenous infusion of ketamine. Subsequent monitoring revealed no exacerbation of psychotic symptoms in short and long-term observation, while stable remission was observed in all cases with imminent antisuicidal effect. Results suggest ketamine may benefit individuals with treatment-resistant depression with psychotic features.

Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis.

Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders.

α-Crystallin chaperone mimetic drugs inhibit lens γ-crystallin aggregation: Potential role for cataract prevention

Γ-Crystallins play a major role in age-related lens transparency. Their destabilization by mutations and physical chemical insults are associated with cataract formation. Therefore, drugs that increase their stability should have anticataract properties. To this end, we screened 2560 Federal Drug Agency–approved drugs and natural compounds for their ability to suppress or worsen H2O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, closantel (C), an antihelminthic drug, and gambogic acid (G), a xanthonoid, attenuated thermal-induced protein unfolding and aggregation as shown by turbidimetry fluorescence spectroscopy dynamic light scattering and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket–binding molecule bis-8-anilino-1-naphthalene sulfonic acid revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins revealed two binding sites, one in the “NC pocket” (residues 50–150) of HγD and one spanning the “NC tail” (residues 56–61 to 168–174 in the C-terminal domain). Multiple binding sites overlap with those of the protective mini αA-crystallin chaperone MAC peptide. Mechanistic studies using bis-8-anilino-1-naphthalene sulfonic acid as a proxy drug showed that it bound to MAC sites, improved Tm of both H2O2 oxidized and native human gamma D, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.

Secondary Infections in Patients with COVID-19 Pneumonia Treated with Tocilizumab Compared to Those Not Treated with Tocilizumab: A Retrospective Study at a Tertiary Hospital in Kenya.

IntroductionFrom the first case of SARS-Co-2 in Wuhan, China, to the virus being declared as a pandemic in March 2020, the world has witnessed morbidity and mortality on a global scale. Scientists have worked at a record pace to deliver a vaccine for the prevention of this deadly disease. Tocilizumab, an interleukin-6 (IL-6) blocker, received an emergency use authorization (EUA) by the Federal Drug Agency (FDA) in June 2021.MethodsThis retrospective observational cohort study was conducted at the Aga Khan University Hospital, Nairobi, from March 8, 2020, to December 31, 2020. All patients with PCR confirmed COVID-19 pneumonia were included. Data were obtained from the medical records, and the admission registry was used to identify the patients, and both their electronic and paper-based files were retrieved from the medical records. Patient demographic data, medical history, baseline comorbidities, clinical characteristics, and outcome data were collected to study the infectious complications of Tocilizumab in patients affected by COVID-19 pneumonia.ResultsA total of 913 patients who were diagnosed with COVID-19 were included. The overall superinfection infection rate among the COVID-19 patients was 6%. Superinfection in patients who received the Tocilizumab was 17.2% and in the non-Tocilizumab group was 4.8%. The superinfection rate among severe and critically ill patients was even higher at 41.8% and 69.9% (Tocilizumab group) and 2.1% and 11.8% (non-Tocilizumab group), respectively (p < 0.001). There was no difference in mortality observed between the groups (p = 0.846). Infection among HIV co-infection was very low at 2.3%.ConclusionContrary to some studies, a higher rate of infection was observed among the Tocilizumab group, and no difference in mortality was observed between Tocilizumab and the non-Tocilizumab group. Infection among patients with HIV remains low in this susceptible population.

Cannabidiol (CBD) use among cancer survivors.

12096 Background: Cannabidiol (CBD) is a non-psychoactive component of cannabis touted for various therapeutic effects. The Federal Drug Agency has only approved one prescription CBD product for treatment of severe epilepsy. On December 17, 2020 the Federal Trade Commission announced legal consequences for deceptively marketed CBD products in the rapidly expanding market of various CBD products; the products’ unsupported claims included CBD as a cancer treatment. Little is known about survivors use of CBD. This study explores the prevalence and nature of CBD use by cancer survivors. Methods: A link to an anonymous, electronic survey was posted on the Levine Cancer Institute and SherryStrong (Martin Truex Jr. Foundation: philanthropy for ovarian cancer) Twitter and Facebook social media platforms. Data were managed in REDCap, a secure, web-based, electronic data capture tool. Survey responses were summarized and described with frequencies and compared using Fisher’s Exact tests; p &lt; 0.1 was considered statistically significant. Results: N = 295 self-selected respondents were White (95%), female (86%), middle aged (45-64 years) (58%) and in the US (95%). Ninety percent indicated current (85%) or past (15%) use of CBD product; a third of these participants (N = 102) identified as cancer survivors. Gynecologic (31%) and breast (30%) cancers were the most recorded malignancies, and 38% report active treatment. Most survivors indicated using CBD products daily (77%) for a year or less (79%) and spent @$30 a week on products (70%). Common uses for CBD were easing pain (66%), anxiety (50%), and sleep (50%)—14% reported treating or preventing cancer. 41% learned about CBD from family/friends, fewer learned from the Internet (21%) or local store (11%). Only 12% received information from a physician. Liquid drops (58%) and topicals (19%) were popular products and reported side effects were sparse—sedation and/or euphoria were indicated by 10% and 2%, respectively. Over 82% of cancer survivors indicated that CBD product helped their conditions. CBD use to ease anxiety and stress declined with age; 71% of young survivors (aged 18-44) sought anxiety relief versus 45% and 36% of middle age (aged 45-64) and seniors (aged 65+), respectively (p = 0.05), and 58% of young survivors pursued stress relief versus 39% of middle age and 21% of seniors (p = 0.08). More young (25%) and middle age (37%) survivors indicated spending over $30 on products weekly than seniors (7%) (p = 0.08). No differences were seen in CBD use between cancer survivors by gender or treatment status. Conclusions: Cancer survivors commonly use CBD, yet infrequently under the guidance of a physician. Survivors largely rely on word of mouth and internet information about CBD. Despite lack of standardization of production and labeling of CBD products, the majority of patients reported positive improvements in symptoms. Future research should explore strategies to educate cancer patients and providers in safe CBD use.

Value for money in genitourinary oncology.

1 Background: Innovation in the treatment of genitourinary (GU) malignancies is accelerating, however, many of these new treatments are often not available for patients. We sought to investigate patient access, cost and value of new systemic anti-cancer compounds (SACTs) in GU oncology. We compared the US and Europe with a focus on the United Kingdom (UK) and the Republic of Ireland (IRL). Methods: Data on licensing and reimbursement decisions was collected on SACTs approved for GU oncology between 01/01/2010 to 09/01/2020. Overall survival (OS) benefit, progression free survival (PFS) benefit and cost of therapy were included in our analysis. Results: There were 29 regimens/indications approved by the Federal Drug Agency (FDA) for GU malignancies between 2010 and 2020. The majority of these (21/29, 72%) were also approved by the European Medicines Agency (EMA). Nearly all regimens/indications were approved by the FDA prior to the EMA (27/29, 93%), with a median time to EMA approval of 4 months (SD = 6, range -6 to 17). Only a minority of these regimens/indications are reimbursed by the public health systems in the UK (12/29, 41%) and IRL (6/29, 21%). Following EMA approval, public reimbursement of these regimens in the UK and IRL is often delayed with a median time of 8 months (+/- 6.3, range 4 - 21) and 11.5 months (+/- 12.5, range 0 - 33) respectively. Approximately half (15/29, 52%) of all reimbursed regimens/indications have demonstrated an overall survival benefit for patients. Androgen signalling inhibitors (ASIs) are more likely to have a proven OS benefit and had a lower mean cost than non-ASI regimens (See Table). A significant minority of regimens/indications (6/29, 21%) have demonstrated neither an OS or PFS benefit. The median price per month (USA list price) was $15,086 +/- $7,019. Regimens with a proven OS benefit were not more expensive than those without ($14,229 +/- $6,466 versus $16,004 +/- $7,704). There was no significant correlation between the length of OS benefit and the cost of regimens (Pearson’s Correlation Coefficient = -2.72, p = 0.445). Conclusions: Patients in the UK and IRL experience clinically significant delays in accessing FDA approved regimens in GU oncology. Only 52% of these regimens have a proven OS benefit. In our study, ASI regimens are cheaper and more effective than non-ASI regimens. There is no association between overall survival benefit and list prices in the USA. We need to radically overhaul licensing and funding of SACTs in GU oncology to ensure continued access for patients to effective medicines. [Table: see text]

Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease.

Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease.

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

Introduction: Diazoxide is the first line and only Federal Drug Agency approved pharmacological agent for the treatment of hyperinsulinism. Its use has increased over the years to include patients with various genetic forms of hyperinsulinism, perinatal stress hyperinsulinism and infants of diabetic mothers with more babies than ever being exposed to this therapy. Methods: We performed a retrospective analysis of 194 patients with hyperinsulinism in our clinic and looked for those who had experienced serious adverse events (SAE) including pulmonary hypertension and neutropenia. We compared the rates of SAE in the different types of hyperinsulinism. Results: Out of 194 patients with hyperinsulinism, 165 (85.1%) were treated with diazoxide. There were 17 SAEs in 16 patients including 8 cases of pulmonary hypertension and 8 of neutropenia. These data show that overall the frequency of SAE associated with diazoxide use is 9.7%, but that those with perinatal stress hyperinsulinism have a much higher rate than those with genetic forms of hyperinsulinism (16.7 vs. 3.6%; p = 0.01). We also found diazoxide is associated with pulmonary hypertension (4.8% of patients treated). Although more patients with perinatal stress hyperinsulinism (7.6%) were affected than genetic hyperinsulinism (1.2%), the difference was not significant (p = 0.088). Conclusion: The rate of SAEs associated with (not necessarily caused by) diazoxide has been demonstrated. The rate of SAE in newborns with perinatal stress hyperinsulinism is significantly higher than that of otherwise healthy babies with genetic forms of hyperinsulinism, suggesting that caution should be used when prescribing diazoxide to this population. This information should help balance the risk benefit of treatment and provide guidance on screening for these complications in the population of treated patients.

Aspiration in injections: should we continue or abandon the practice?

Aspiration during any kind of injection is meant to ensure that the needle tip is at the desired location during this blind procedure. While aspiration appears to be a simple procedure, it has generated a lot of controversy concerning the perceived benefits and indications. Advocates and opponents of aspiration both make logically sound claims. However, due to scarcity of available data, there is no evidence that this procedure is truly beneficial or unwarranted. Keeping in view the huge number of injections given worldwide, it is important that we draw attention to key questions regarding aspiration that, up till now, remain unanswered. In this review, we have attempted to gather and present literature on aspiration both from published and non-published sources in order to provide not only an exhaustive review of the subject, but also a starting point for further studies on more specific areas requiring clarification. A literature review was conducted using the US National Institute of Health’s PubMed service (including Medline), Google Scholar and Scopus. Guidelines provided by the World Health Organization, Safe Injection Global Network, International Council of Nursing, Center for Disease Control, US Federal Drug Agency, UK National Health Services, British Medical Association, Europe Nursing and Midwifery Council, Public Health Agency Canada, Pakistan Medical Association and International Organization of Standardization recommendations 7886 parts 1-4 for sterile hypodermics were reviewed for relevant information. In addition, curricula of several medical/nursing schools from India, Nigeria and Pakistan, the US pharmacopeia Data from the WHO Program for International Drug Monitoring network in regard to adverse events as a result of not aspirating prior to injection delivery were reviewed. Curricula of selected major medical/nursing schools in India, Nigeria and Pakistan, national therapeutic formularies, product inserts of most commonly used drugs and other possible sources of information regarding aspiration and injections were consulted as well.

Aspiration in injections: should we continue or abandon the practice?

Aspiration during any kind of injection is meant to ensure that the needle tip is at the desired location during this blind procedure. While aspiration appears to be a simple procedure, it has generated a lot of controversy concerning the perceived benefits and indications. Advocates and opponents of aspiration both make logically sound claims. However, due to scarcity of available data, there is no evidence that this procedure is truly beneficial or unwarranted. Keeping in view the huge number of injections given worldwide, it is important that we draw attention to key questions regarding aspiration that, up till now, remain unanswered. In this review, we have attempted to gather and present literature on aspiration both from published and non-published sources in order to provide not only an exhaustive review of the subject, but also a starting point for further studies on more specific areas requiring clarification. A literature review was conducted using the US National Institute of Health’s PubMed service (including Medline), Google Scholar and Scopus. Guidelines provided by the World Health Organization, Safe Injection Global Network, International Council of Nursing, Center for Disease Control, US Federal Drug Agency, UK National Health Services, British Medical Association, Europe Nursing and Midwifery Council, Public Health Agency Canada, Pakistan Medical Association and International Organization of Standardization recommendations 7886 parts 1-4 for sterile hypodermics were reviewed for relevant information. In addition, curricula of several medical/-nursing schools from India, Nigeria and Pakistan, the US pharmacopeia Data from the WHO Program for International Drug Monitoring network in regard to adverse events as a result of not aspirating prior to injection delivery were reviewed. Curricula of selected major medical/nursing schools in India, Nigeria and Pakistan, national therapeutic formularies, product inserts of most commonly used drugs and other possible sources of information regarding aspiration and injections were consulted as well.

Analysis of the safety evaluation for premarketing clinical trials of hemodialyzer and of postmarketing safety reports of hemodialyzer in Japan and the US: insights into the construction of a sophisticated premarketing evaluation.

Our aim was to conduct a scoping review of the regulations for hemodialyzers in the safety evaluation in Japan and the United States, and to evaluate the criteria for premarketing clinical trials and postmarketing safety reports to inform the development of a sophisticated premarketing evaluation in Japan. Regulations for approval of hemodialyzers were identified from the databases of the Ministry of Health, Labor and Welfare in Japan and the Federal Drug Agency (FDA) in the United States (US). The criteria for premarket clinical trials and postmarketing safety reports were evaluated for both countries. Standards in Japan required evaluation of blood compatibility and reporting of acute adverse effects by a premarketing clinical trial in 6 of 86 applications with semipermeable membrane materials deemed to be different to those of previously approved devices from 1983 to 31 August 2015. By comparison, the clinical trial was required in one of 545 approvals in the US from 1976 to 29 January 2016, but blood compatibility was not the point. All postmarketing adverse effects identified in Japan were included in the set of 'warnings'. The more stringent requirements for evaluation of blood compatibility and acute adverse effects in Japan seemed to be related to differences in the history of quality management systems for medical devices between the two countries. This study revealed that there were differences between Japan and the US in requiring the premarketing clinical trials for the hemodialyzers. Our findings could be useful for constructing sophisticated premarketing safety evaluation.

Laboratory Safety of Capsaicin Inhalation in Healthy Younger and Older Populations Potential Template for Inhalation Research

Introduction: There are inconsistencies as to the effects of age on the human cough reflex. The investigation speaks to the Federal Drug Agency’s (FDA) trepidations for conducting inhalation experiments with non-approved medications/chemicals. The investigation addresses the accuracy of the mixing methodology and analysis of capsaicin stability during seven months of storage. Methods: There is stringent safety monitoring while conducting 12 serial (0.49-1000 uMol) single breath capsaicin inhalation challenge testing (CICT) on 20 younger and 20 older healthy research volunteers using pharmaceutical-grade capsaicin (i.e., Investigational New Drug protocol-IND 69,642). The research design and subject safety measures are recommended by the Food & Drug Agency (FDA) and approved by the Institutional Review Board (IRB). Mixing of inhaled capsaicin solutions are by a Registered Pharmacist and concentration verifications are by high performance liquid chromatography (HPLC). Potency of stored capsaicin (i.e., refrigerated and shielded from UV light) is examined over 7 months. Results: There are neither adverse reactions nor statistically significant difference in capsaicin cough parameters for older and younger volunteers at any dose of capsaicin. Physiologic monitoring by spirometry, impulse oscillometry, exhaled breath nitric oxide, electrocardiography, blood pressure, pulse and oxygen saturation measurements do not change at any dose. There are differences between the concentrations of capsaicin solutions mixed by a Registered Pharmacist and actual capsaicin determination by HPLC. The differences in capsaicin concentrations are 28.1% lower for 0.49 uMol compared to a 2.2% lesser concentration for 1000 uMol solution. During storage, capsaicin remains stable for 3-months but substantially falls by six (p<0.03) and seven (p<0.004) months, especially for the lower concentrations. Conclusion: The results of this investigation embrace the safety of serial Inhalations of dilute pharmacologic grade capsaicin aerosol among older and younger normal volunteers. Incorporating rigorous FDA recommendations, inclusion of IRB oversight and monitoring by spirometry, impulse oscillometry, exhaled breath nitric oxide, electrocardiography, blood pressure, pulse and oxygen saturation measurements document inhalation safety at any dilute capsaicin aerosol dose. However, there are lower capsaicin values determined by HPLC compared to expected capsaicin concentrations when mixed by a Registered Pharmacist or after six months of storage. The investigation champions the opinion that inhalation studies involving FDA non-approved drugs or chemicals/ medications can be safely conducted when following the appropriate safety procedures such as in this research protocol.

Noncoding RNAs: the fourth dimension of the human genome

amount of the transcriptome in biology is however, unclear. This part of the genome, the noncoding RNAs (ncRNAs) can be rightly be considered the fourth dimension of the genome. The ncRNAs comprise the long non-coding RNAs (lncRNAs), the long intergenic RNAs (lincRNAs), endogenous antisense RNAs, the microRNAs (miRs) and pseudogenes-derived lncRNAs [7]. The current version of the GENCODE database (v 22) estimates there to be 25,794 ncRNAs in humans [11,12]. The ncRNAs are crucial in gene regulation exerting their regulatory role at the chromatin, transcriptome and proteome level [13]. The regulation of the target genes by the ncRNAs occurs at the level of RNA and protein stabilization, protein binding and protein translocation or processing [9].Originally thought to be non-protein coding transcripts, at least some of the ncRNAs now seem to be capable of coding for Open Reading Frames [14,15]. Thus, eventually the terminology non-coding will have to evolve to accurately reflect the differences between the coding and the non-coding nature of the transcriptome. Increasing evidence in the ncRNA field of research is beginning to challenge our current understanding of the human genome. Pseudogene-derived lncRNAs are emerging as key regulators of gene expression and as a reservoir for miRs and endogenous antisense transcripts [16]. In addition, various Genome Wide Association Studies (GWAS) have identified a vast majority of disease-associated Single Nucleotide Polymorphisms (SNPs) which are present at the non-coding intronic or intergenic regions of the genes [17,18]. These regions were neglected in the past because of the focus on the protein coding regions. However, the attention is beginning to shift to this unexplored region of the human genome. Understanding the impact of these SNPs is going to allow us to develop a better understanding of diverse disease-associated phenotypes in the future. The ncRNAs including the miRs are of major interest for novel therapeutics as well as diagnostic biomarker development [4,19,20]. Numerous tools are becoming available to study the ncRNAs [21-26]. A microRNAs miR 222, is being developed as a therapeutic for hepatocellular carcinoma [27]. The Federal Drug Agency (FDA) approved its first lncRNA, the Prostate cancer antigen 3 (PCA3) as a urinary biomarker for prostate cancer diagnosis [28]. The miRs because of the stability in body fluids due to the secretome nature involving the exosomes, offer tremendous opportunities for biomarker potential for diagnosis and prognosis for cancer and other diseases [19,29-31]. The ncRNAs are the next frontier in molecular biology. The fruits of research in the ncRNA arena in the next decade are likely to challenge the current dogma in molecular biology. As we begin to understand more about the role of the entire transcriptome in gene regulation, our understanding of biology and function of a gene will achieve greater clarity. This is likely to lead into novel therapy and diagnosis for diverse diseases.