Does millet consumption contribute to raising blood hemoglobin levels compared to regular refined staples?: a systematic review and meta-analysis.

Millets are recognized for their health and nutritional values, and the United Nations declared 2023 the International Year of Millets. Among the several health and nutritional benefits of millets, their impact on hemoglobin concentration is important since anemia is a major public health issue in many countries. To investigate the effect of millet (including sorghum) consumption on hemoglobin concentration in the blood, a systematic review and meta-analysis were conducted. Thirteen published studies featuring randomized control trials involving 590 individuals in the intervention group and 549 control individuals were eligible for the meta-analysis. The difference-in-differences analysis revealed highly significant (p < 0.01) positive effects of millet consumption on hemoglobin concentration, with an effect size of +0.68 standardized mean difference units. The change in hemoglobin concentration observed in the intervention group was +13.6%, which is statistically significant (p < 0.0005), compared to that in the control group, which was +4.8% and not statistically significant (p = 0.1362). In four studies, the consumption of millets in the intervention group demonstrated a change from mild anemia to normal status among children, whereas there was no change in the control group. The findings provide evidence that the consumption of millets can improve blood hemoglobin concentration, likely resulting from increased iron intake. Further research is needed involving the assessment of iron content and bioavailability to better understand the effect variation among millet types and the mechanisms involved.

Comparison of a Novel, Flavor-optimized, Polyethylene Glycol and Sulfate Bowel Preparation With Oral Sulfate Solution in Adults Undergoing Colonoscopy.

INTRODUCTION: A new bowel preparation for colonoscopy has been developed containing poorly absorbed sulfate salts and polyethylene glycol 3350, which retain water within the intestinal lumen resulting in copious diarrhea, thereby cleansing the bowel. The product was formulated to be safe and effective with a sports drink-like flavor. This study evaluated the new flavored polyethylene glycol and sulfate solution (FPSS) compared with a Food and Drug Administration-approved bowel preparation containing sulfate salts only [oral sulfate solution (OSS)]. METHODS: Five hundred adults were enrolled in this multicenter, noninferiority study. Subjects were assigned FPSS or OSS administered in split-dose regimens (PM/AM). FPSS subjects took 2 L of the flavored osmotic solution (1 L at night and 1 L in the morning). OSS was taken according to its approved labeling. Colonoscopies were graded globally and segmentally by blinded local investigators using a 4-point scale (excellent, good, fair, and poor), with "good" and "excellent" considered successful. Safety was assessed by adverse events (AEs) and laboratory testing. RESULTS: A high rate of cleansing success was seen with FPSS (94%), which was noninferior to OSS (94%). This conclusion was confirmed by blinded central readers. Segmental success rates were >90% for both preparations, including the right colon. Questionnaire ratings indicated the FPSS experience was preferred over OSS with 87% of FPSS subjects noting their preparation was "tolerable" to "very easy" to consume versus 74% for OSS. The majority of FPSS subjects agreed their preparation tasted like a sports drink. Gastrointestinal symptoms were the most common AEs. There was no difference between preparations for any AE and no clinically significant differences in laboratory parameters. CONCLUSIONS: The new sports drink-like flavored preparation achieved a high level of cleansing in the study, demonstrating noninferiority to OSS. FPSS was well-tolerated with low rates of expected gastrointestinal symptoms. The optimized flavor of FPSS resulted in significantly better acceptance ratings.

Can Feeding a Millet-Based Diet Improve the Growth of Children?-A Systematic Review and Meta-Analysis.

Undernutrition, such as stunting and underweight, is a major public health concern, which requires multi-sectoral attention. Diet plays a key role in growth and should optimally supply all required nutrients to support the growth. While millets (defined broadly to include sorghum) are traditional foods, and climate smart nutritious crops, which are grown across Africa and Asia, they have not been mainstreamed like rice, wheat, and maize. Diversifying staples with millets can potentially provide more macro and micro nutrients, compared to the mainstream crops. However, there is little known scientific evidence to prove millets' efficacy on growth. Therefore, a systematic review and meta-analysis was conducted to collate evidence of the benefits of millets in improving the growth of children. Eight eligible randomized feeding trials were included in the meta-analysis. Results from the randomized effect model showed a significant effect (p < 0.05) of millet-based diets on mean height (+28.2%) (n = 8), weight (n = 9) (+26%), mid upper arm circumference (n = 5) (+39%) and chest circumference (n = 5) (+37%) in comparison to regular rice-based diets over for the period of 3 months to 4.5 years, which was based on largely substituting rice with millets. When an enhanced and diverse diet was served, replacing rice with millet had only minimal growth improvement on chest circumference (p < 0.05). The quality assessment using GRADE shows that the evidence used for this systematic review and meta-analysis had moderate quality, based on eight scoring criteria. These results demonstrate the value of adding millet as the staple for undernourished communities. Further understanding of the efficacy of millets on growth in a wider range of diets is important to develop appropriate dietary programs and improve the nutritional status of various age groups across Africa and Asia.

Millets Can Have a Major Impact on Improving Iron Status, Hemoglobin Level, and in Reducing Iron Deficiency Anemia-A Systematic Review and Meta-Analysis.

The prevalence of iron deficiency anemia is highest among low and middle-income countries. Millets, including sorghum, are a traditional staple in many of these countries and are known to be rich in iron. However, a wide variation in the iron composition of millets has been reported, which needs to be understood in consonance with its bioavailability and roles in reducing anemia. This systematic review and meta-analysis were carried out to analyze the scientific evidence on the bioavailability of iron in different types of millets, processing, and the impact of millet-based food on iron status and anemia. The results indicated that iron levels in the millets used to study iron bioavailability (both in vivo and in vitro) and efficacy varied with the type and variety from 2 mg/100 g to 8 mg/100 g. However, not all the efficacy studies indicated the iron levels in the millets. There were 30 research studies, including 22 human interventions and 8 in vitro studies, included in the meta-analysis which all discussed various outcomes such as hemoglobin level, serum ferritin level, and absorbed iron. The studies included finger millet, pearl millet, teff and sorghum, or a mixture of millets. The results of 19 studies conducted on anaemic individuals showed that there was a significant (p < 0.01) increase in hemoglobin levels by 13.2% following regular consumption (21 days to 4.5 years) of millets either as a meal or drink compared with regular diets where there was only 2.7% increase. Seven studies on adolescents showed increases in hemoglobin levels from 10.8 ± 1.4 (moderate anemia) to 12.2 ± 1.5 g/dl (normal). Two studies conducted on humans demonstrated that consumption of a pearl millet-based meal significantly increased the bioavailable iron (p < 0.01), with the percentage of bioavailability being 7.5 ± 1.6, and provided bioavailable iron of 1 ± 0.4 mg. Four studies conducted on humans showed significant increases in ferritin level (p < 0.05) up to 54.7%. Eight in-vitro studies showed that traditional processing methods such as fermentation and germination can improve bioavailable iron significantly (p < 0.01) by 3.4 and 2.2 times and contributed to 143 and 95% of the physiological requirement of women, respectively. Overall, this study showed that millets can reduce iron deficiency anemia.

Can Millet Consumption Help Manage Hyperlipidemia and Obesity?: A Systematic Review and Meta-Analysis.

Many health benefits of millets (defined broadly to also include sorghum) have been advocated, including their roles in managing and preventing diabetes; however, the effects of millets on hyperlipidemia (high lipid levels) have been underrecognized. A systematic review and meta-analysis were conducted to collate available evidence of the impacts of millets consumption on lipid profile, namely total cholesterol (TC), triacylglycerol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C). The results from 19 studies showed that the consumption of millets for periods as short as 21 days to 4 months reduced levels of TC, triacylglycerol, LDL-C, and VLDL-C (p<0.01) by 8.0, 9.5, 10 and 9.0%, respectively. Four studies demonstrated that millets consumption brought TC and triacylglycerol levels to the normal levels (<200 and <150 mg/dl, respectively). Furthermore, upon consumption of millet-based meals, there was a 6.0% increase in the HDL-C 4.0 and 5.0% reduction in systolic and diastolic blood pressure, and 7.0% reduction in body mass index (BMI). This evidence, leads us to conclude that consumption of millets reduces hyperlipidemia and hence hypertension, and raises the levels of HDL-C (good cholesterol), which can be beneficial for managing the associated risk of developing hypertension and atherosclerotic cardiovascular diseases in future. Systematic Review Registration: The protocol of this systematic review has been registered in the online registration platform called "research registry" with the unique identification number "reviewregistry1123."

PTG-100, an Oral α4ß7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis.

BACKGROUND & AIMS: Oral therapies targeting the integrin α4ß7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4ß7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). METHODS: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. RESULTS: PTG-100 potently and selectively blocks α4ß7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. CONCLUSIONS: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4ß7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75).

A Systematic Review and Meta-Analysis of the Potential of Millets for Managing and Reducing the Risk of Developing Diabetes Mellitus.

Millets (including sorghum) are known to be highly nutritious besides having a low carbon footprint and the ability to survive in high temperatures with minimal water. Millets are widely recognised as having a low Glycaemic Index (GI) helping to manage diabetes. This systematic review and meta-analyzes across the different types of millets and different forms of processing/cooking collated all evidences. Of the 65 studies that were collected globally, 39 studies with 111 observations were used to analyze GI outcomes and 56 studies were used to analyze fasting, post-prandial glucose level, insulin index and HbA1c outcomes in a meta-analysis. It is evident from the descriptive statistics that the mean GI of millets is 52.7 ± 10.3, which is about 36% lower than in typical staples of milled rice (71.7 ± 14.4) and refined wheat (74.2 ± 14.9). The descriptive, meta and regression analyses revealed that Job's tears, fonio, foxtail, barnyard, and teff were the millets with low mean GI (<55) that are more effective (35-79%) in reducing dietary GI than the control samples. Millets with intermediate GI (55-69) are pearl millet, finger millet, kodo millet, little millet, and sorghum which have a 13-35% lower GI than the control with high GI (>69). A meta-analysis also showed that all millets had significantly (p < 0.01) lower GI than white rice, refined wheat, standard glucose or white wheat bread except little millet which had inconsistent data. Long term millet consumption lowered fasting and post-prandial blood glucose levels significantly (p < 0.01) by 12 and 15%, respectively, in diabetic subjects. There was a significant reduction in HbA1c level (from 6.65 ± 0.4 to 5.67 ± 0.4%) among pre-diabetic individuals (p < 0.01) who consumed millets for a long period. Minimally processed millets were 30% more effective in lowering GI of a meal compared to milled rice and refined wheat. In conclusion, millets can be beneficial in managing and reducing the risk of developing diabetes and could therefore be used to design appropriate meals for diabetic and pre-diabetic subjects as well as for non-diabetic people for a preventive approach.

A Safety and Efficacy Comparison of a New Sulfate-Based Tablet Bowel Preparation Versus a PEG and Ascorbate Comparator in Adult Subjects Undergoing Colonoscopy.

INTRODUCTION: A new tablet-based bowel prep for colonoscopy has been developed containing poorly absorbed sulfate salts which act to retain water within the intestinal lumen resulting in a copious diarrhea, thereby cleansing the bowel. This study evaluated the safety and efficacy of these oral sulfate tablets (OST) compared with a US FDA-approved bowel prep solution containing PEG3350, electrolytes, and ascorbate (polyethylene glycol and ascorbate [PEG-EA]). METHODS: Five hundred fifteen adult patients (mean 57y) were enrolled in this single-blind, multicenter, noninferiority study. Subjects were assigned either PEG-EA or OST to be administered in a split-dose regimen starting the evening before colonoscopy. PEG-EA was taken according to its approved labeling (1 L of prep solution with 16 oz. of additional water) in the evening and again in the morning. OST patients took a total of 24 tablets. OST patients were administered 12 tablets in the evening, and the following morning. Patients consumed 16 ounces of water with each dose of 12 tablets and drank an additional 32 oz. of water with each dose. Colonoscopies were performed by blinded investigators. Cleansing efficacy was evaluated globally and segmentally using a 4-point scale (Excellent-no more than small bits of feces/fluid which can be suctioned easily; achieves clear visualization of the entire colonic mucosa. Good-feces and fluid requiring washing and suctioning, but still achieves clear visualization of the entire colonic mucosa. Fair-enough feces even after washing and suctioning to prevent clear visualization of the entire colonic mucosa. Poor-large amounts of fecal residue and additional bowel preparation required). Scores of Good or Excellent were considered to be a success. Safety was assessed by spontaneously reported adverse events, solicited ratings of expected prep symptoms, and laboratory testing. RESULTS: A high rate of cleansing success was seen with OST (92%), which was noninferior to PEG-EA (89%). Only a small proportion of subjects rated their expected gastrointestinal symptoms as severe (<5% for both preps). No clinically significant differences were seen between preps for chemistry and hematology parameters. No serious adverse experiences were reported with OST. DISCUSSION: Sulfate tablets achieved a high level of cleansing in the study, comparable with US FDA-approved preps. OST was noninferior to PEG-EA in this study and achieved significantly more Excellent preps overall and in the proximal colon. The OST prep was well-tolerated, with a similar rate of spontaneously reported adverse experiences to PEG-EA and a low rate of severe expected gastrointestinal symptoms.

Safety and efficacy of remimazolam in high risk colonoscopy: A randomized trial.

BACKGROUND: Procedural sedation of ASA III/IV patients has increased risk. Remimazolam (an ultra-short-acting benzodiazepine) has proven safe and efficient for outpatient colonoscopy sedation. METHODS: A double-blind, randomized, multi-center, parallel group trial was performed, comparing remimazolam to placebo with an additional open-label arm for midazolam in procedural sedation of 79 ASA III/IV patients undergoing colonoscopy. This was the third of 3 Phase III trials for remimazolam in the procedural sedation program. The primary end point was the safety of remimazolam. RESULTS: Of 79 patients randomized at 3 US sites, 77 underwent sedation and colonoscopy (31 received remimazolam, 16 placebo and 30 midazolam). Incidence and frequency of treatment emergent adverse events (TEAEs) were comparable in all three treatment arms, and independent of ASA status. One TEAE leading to discontinuation and one serious TEAE were reported; both in the open label midazolam arm. The efficacy endpoint was achieved for remimazolam, placebo, and midazolam in 87.1%, 0%, and 13.3% of patients (p<0.00001 for remimazolam versus placebo and versus midazolam, respectively). CONCLUSIONS: Remimazolam is safe and efficient in procedural sedation of high risk ASA patients undergoing colonoscopy, showing a safety profile comparable to that in low risk ASA.

Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme.

BACKGROUND AND AIMS: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC. METHODS: TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. RESULTS: TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. CONCLUSION: Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686].

A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy.

BACKGROUND AND AIMS: Remimazolam is an ultrashort-acting benzodiazepine. METHODS: We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (the randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 µg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator's discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and ≤5 doses of remimazolam or placebo in any 15-minute interval (≤3 doses of midazolam in any 12-minute interval in the open-label midazolam arm). RESULTS: There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P < .0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge earlier, and felt back to normal sooner than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam, and hypoxia occurred in 1% of patients with remimazolam or midazolam. There were no treatment-emergent serious adverse events. CONCLUSION: Remimazolam can be administered safely under the supervision of endoscopists for outpatient colonoscopy, and it allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. (Clinical trial registration number: NCT02290873.).

Cyanide toxicokinetics: the behavior of cyanide, thiocyanate and 2-amino-2-thiazoline-4-carboxylic acid in multiple animal models.

Cyanide causes toxic effects by inhibiting cytochrome c oxidase, resulting in cellular hypoxia and cytotoxic anoxia, and can eventually lead to death. Cyanide exposure can be verified by direct analysis of cyanide concentrations or analyzing its metabolites, including thiocyanate (SCN(-)) and 2-amino-2-thiazoline-4-carboxylic acid (ATCA) in blood. To determine the behavior of these markers following cyanide exposure, a toxicokinetics study was performed in three animal models: (i) rats (250-300 g), (ii) rabbits (3.5-4.2 kg) and (iii) swine (47-54 kg). Cyanide reached a maximum in blood and declined rapidly in each animal model as it was absorbed, distributed, metabolized and eliminated. Thiocyanate concentrations rose more slowly as cyanide was enzymatically converted to SCN(-). Concentrations of ATCA did not rise significantly above the baseline in the rat model, but rose quickly in rabbits (up to a 40-fold increase) and swine (up to a 3-fold increase) and then fell rapidly, generally following the relative behavior of cyanide. Rats were administered cyanide subcutaneously and the apparent half-life (t1/2) was determined to be 1,510 min. Rabbits were administered cyanide intravenously and the t1/2 was determined to be 177 min. Swine were administered cyanide intravenously and the t1/2 was determined to be 26.9 min. The SCN(-) t1/2 in rats was 3,010 min, but was not calculated in rabbits and swine because SCN(-) concentrations did not reach a maximum. The t1/2 of ATCA was 40.7 and 13.9 min in rabbits and swine, respectively, while it could not be determined in rats with confidence. The current study suggests that cyanide exposure may be verified shortly after exposure by determining significantly elevated cyanide and SCN(-) in each animal model and ATCA may be used when the ATCA detoxification pathway is significant.

Development of a fluorescence-based sensor for rapid diagnosis of cyanide exposure.

Although commonly known as a highly toxic chemical, cyanide is also an essential reagent for many industrial processes in areas such as mining, electroplating, and synthetic fiber production. The "heavy" use of cyanide in these industries, along with its necessary transportation, increases the possibility of human exposure. Because the onset of cyanide toxicity is fast, a rapid, sensitive, and accurate method for the diagnosis of cyanide exposure is necessary. Therefore, a field sensor for the diagnosis of cyanide exposure was developed based on the reaction of naphthalene dialdehyde, taurine, and cyanide, yielding a fluorescent ß-isoindole. An integrated cyanide capture "apparatus", consisting of sample and cyanide capture chambers, allowed rapid separation of cyanide from blood samples. Rabbit whole blood was added to the sample chamber, acidified, and the HCN gas evolved was actively transferred through a stainless steel channel to the capture chamber containing a basic solution of naphthalene dialdehyde (NDA) and taurine. The overall analysis time (including the addition of the sample) was <3 min, the linear range was 3.13-200 µM, and the limit of detection was 0.78 µM. None of the potential interferents investigated (NaHS, NH4OH, NaSCN, and human serum albumin) produced a signal that could be interpreted as a false positive or a false negative for cyanide exposure. Most importantly, the sensor was 100% accurate in diagnosing cyanide poisoning for acutely exposed rabbits.

Simultaneous high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analysis of cyanide and thiocyanate from swine plasma.

An analytical procedure for the simultaneous determination of cyanide and thiocyanate in swine plasma was developed and validated. Cyanide and thiocyanate were simultaneously analyzed by high-performance liquid chromatography tandem mass spectrometry in negative ionization mode after rapid and simple sample preparation. Isotopically labeled internal standards, Na(13)C(15)N and NaS(13)C(15)N, were mixed with swine plasma (spiked and nonspiked), proteins were precipitated with acetone, the samples were centrifuged, and the supernatant was removed and dried. The dried samples were reconstituted in 10 mM ammonium formate. Cyanide was reacted with naphthalene-2,3-dicarboxaldehyde and taurine to form N-substituted 1-cyano[f]benzoisoindole, while thiocyanate was chemically modified with monobromobimane to form an SCN-bimane product. The method produced dynamic ranges of 0.1-50 and 0.2-50 µM for cyanide and thiocyanate, respectively, with limits of detection of 10 nM for cyanide and 50 nM for thiocyanate. For quality control standards, the precision, as measured by percent relative standard deviation, was below 8 %, and the accuracy was within ±10 % of the nominal concentration. Following validation, the analytical procedure successfully detected cyanide and thiocyanate simultaneously from the plasma of cyanide-exposed swine.

Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. METHODS: In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14-18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. RESULTS: A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of -7.0 mm in favor of NTG 0.4% (95% CI -13.6, -0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. CONCLUSIONS: This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00522041.

Toxicokinetic profiles of α-ketoglutarate cyanohydrin, a cyanide detoxification product, following exposure to potassium cyanide.

Poisoning by cyanide can be verified by analysis of the cyanide detoxification product, α-ketoglutarate cyanohydrin (α-KgCN), which is produced from the reaction of cyanide and endogenous α-ketoglutarate. Although α-KgCN can potentially be used to verify cyanide exposure, limited toxicokinetic data in cyanide-poisoned animals are available. We, therefore, studied the toxicokinetics of α-KgCN and compared its behavior to other cyanide metabolites, thiocyanate and 2-amino-2-thiazoline-4-carboxylic acid (ATCA), in the plasma of 31 Yorkshire pigs that received KCN (4mg/mL) intravenously (IV) (0.17 mg/kg/min). α-KgCN concentrations rose rapidly during KCN administration until the onset of apnea, and then decreased over time in all groups with a half-life of 15 min. The maximum concentrations of α-KgCN and cyanide were 2.35 and 30.18 µM, respectively, suggesting that only a small fraction of the administered cyanide is converted to α-KgCN. Although this is the case, the α-KgCN concentration increased >100-fold over endogenous concentrations compared to only a three-fold increase for cyanide and ATCA. The plasma profile of α-KgCN was similar to that of cyanide, ATCA, and thiocyanate. The results of this study suggest that the use of α-KgCN as a biomarker for cyanide exposure is best suited immediately following exposure for instances of acute, high-dose cyanide poisoning.

Simultaneous determination of cyanide and thiocyanate in plasma by chemical ionization gas chromatography mass-spectrometry (CI-GC-MS).

An analytical method utilizing chemical ionization gas chromatography-mass spectrometry was developed for the simultaneous determination of cyanide and thiocyanate in plasma. Sample preparation for this analysis required essentially one-step by combining the reaction of cyanide and thiocyanate with pentafluorobenzyl bromide and simultaneous extraction of the product into ethyl acetate facilitated by a phase-transfer catalyst, tetrabutylammonium sulfate. The limits of detection for cyanide and thiocyanate were 1 µM and 50 nM, respectively. The linear dynamic range was from 10 µM to 20 mM for cyanide and from 500 nM to 200 µM for thiocyanate with correlation coefficients higher than 0.999 for both cyanide and thiocyanate. The precision, as measured by %RSD, was below 9 %, and the accuracy was within 15 % of the nominal concentration for all quality control standards analyzed. The gross recoveries of cyanide and thiocyanate from plasma were over 90 %. Using this method, the toxicokinetic behavior of cyanide and thiocyanate in swine plasma was assessed following cyanide exposure.

Plasma persistence of 2-aminothiazoline-4-carboxylic acid in rat system determined by liquid chromatography tandem mass spectrometry.

2-Aminothiazoline-4-carboxylic acid (ATCA) was intravenously injected to rats in order to investigate its plasma distribution. ATCA was extracted from plasma samples by solid phase extraction (SPE) and molecularly imprinted polymer stir bar sorption extraction (MIP-SBSE). Detection and quantification of ATCA were achieved by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). It was found that the intravenously injected ATCA concentration quickly decreased to half within 2.5h in the rat system. However, after 2.5 h, the concentration of ATCA in plasma stayed constant at least 5 folds above the endogenous ATCA level for more then 48 h. This finding can be used for evaluating ATCA's diagnostic and forensic value as a biomarker for cyanide exposure.