High-Flow Oxygen and High-Flow Air for Dyspnea in Hospitalized Patients with Cancer: A Pilot Crossover Randomized Clinical Trial.

BACKGROUND: The effect of high-flow oxygen (HFOx) and high-flow air (HFAir) on dyspnea in nonhypoxemic patients is not known. We assessed the effect of HFOx, HFAir, low-flow oxygen (LFOx), and low-flow air (LFAir) on dyspnea. SUBJECTS, MATERIALS, AND METHODS: This double-blind, 4×4 crossover clinical trial enrolled hospitalized patients with cancer who were dyspneic at rest and nonhypoxemic (oxygen saturation >90% on room air). Patients were randomized to 10 minutes of HFOx, HFAir, LFOx, and LFAir in different orders. The flow rate was titrated between 20-60 L/minute in the high-flow interventions and 2 L/minute in the low-flow interventions. The primary outcome was dyspnea numeric rating scale (NRS) "now" where 0 = none and 10 = worst. RESULTS: Seventeen patients (mean age 51 years, 58% female) completed 55 interventions in a random order. The absolute change of dyspnea NRS between 0 and 10 minutes was -1.8 (SD 1.7) for HFOx, -1.8 (2.0) for HFAir, -0.5 (0.8) for LFOx, and - 0.6 (1.2) for LFAir. In mixed model analysis, HFOx provided greater dyspnea relief than LFOx (mean difference [95% confidence interval] -0.80 [-1.45, -0.15]; p = .02) and LFAir (-1.24 [-1.90, -0.57]; p < .001). HFAir also provided significantly greater dyspnea relief than LFOx (-0.95 [-1.61, -0.30]; p = .005) and LFAir (-1.39 [-2.05, -0.73]; p < .001). HFOx was well tolerated. Seven (54%) patients who tried all interventions blindly preferred HFOx and four (31%) preferred HFAir. CONCLUSION: We found that HFOx and HFAir provided a rapid and clinically significant reduction of dyspnea at rest in hospitalized nonhypoxemic patients with cancer. Larger studies are needed to confirm these findings (Clinicaltrials.gov: NCT02932332). IMPLICATIONS FOR PRACTICE: This double-blind, 4×4 crossover trial examined the effect of oxygen or air delivered at high- or low-flow rates on dyspnea in hospitalized nonhypoxemic patients with cancer. High-flow oxygen and high-flow air were significantly better at reducing dyspnea than low-flow oxygen/air, supporting a role for palliation beyond oxygenation.

High-Flow Nasal Cannula Therapy for Exertional Dyspnea in Patients with Cancer: A Pilot Randomized Clinical Trial.

BACKGROUND: Exertional dyspnea is common in patients with cancer and limits their function. The impact of high-flow nasal cannula on exertional dyspnea in nonhypoxemic patients is unclear. In this double-blind, parallel-group, randomized trial, we assessed the effect of flow rate (high vs. low) and gas (oxygen vs. air) on exertional dyspnea in nonhypoxemic patients with cancer. PATIENTS AND METHODS: Patients with cancer with oxygen saturation >90% at rest and exertion completed incremental and constant work (80% maximal) cycle ergometry while breathing low-flow air at 2 L/minute. They were then randomized to receive high-flow oxygen, high-flow air, low-flow oxygen, or low-flow air while performing symptom-limited endurance cycle ergometry at 80% maximal. The primary outcome was modified 0-10 Borg dyspnea intensity scale at isotime. Secondary outcomes included dyspnea unpleasantness, exercise time, and adverse events. RESULTS: Seventy-four patients were enrolled, and 44 completed the study (mean age 63; 41% female). Compared with low-flow air at baseline, dyspnea intensity was significantly lower at isotime with high-flow oxygen (mean change, -1.1; 95% confidence interval [CI], -2.1, -0.12) and low-flow oxygen (-1.83; 95% CI, -2.7, -0.9), but not high-flow air (-0.2; 95% CI, -0.97, 0.6) or low-flow air (-0.5; 95% CI, -1.3, 0.4). Compared with low-flow air, high-flow oxygen also resulted in significantly longer exercise time (difference + 2.5 minutes, p = .009), but not low-flow oxygen (+0.39 minutes, p = .65) or high-flow air (+0.63 minutes, p = .48). The interventions were well tolerated without significant adverse effects. CONCLUSION: Our preliminary findings support that high-flow oxygen improved both exertional dyspnea and exercise duration in nonhypoxemic patients with cancer. (ClinicalTrials.gov ID: NCT02357134). IMPLICATIONS FOR PRACTICE: In this four-arm, double-blind, randomized clinical trial examining the role of high-flow nasal cannula on exertional dyspnea in patients with cancer without hypoxemia, high-flow oxygen, but not high-flow air, resulted in significantly lower dyspnea scores and longer exercise time. High-flow oxygen delivered by high-flow nasal cannula devices may improve clinically relevant outcomes even in patients without hypoxemia.

Mental health interventions in schools in low-income and middle-income countries.

Increasing enrolment rates could place schools in a crucial position to support mental health in low-income and middle-income countries. In this Review, we provide evidence for mental health interventions in schools in accordance with a public mental health approach spanning promotion, prevention, and treatment. We identified a systematic review for mental health promotion, and identified further prevention and treatment studies. Present evidence supports schools as places for promotion of positive aspects of mental health using a whole-school approach. Knowledge of effectiveness of prevention and treatment interventions is more widely available for conflict-affected children and adolescents. More evidence is needed to identify the many elements likely to be associated with effective prevention and treatment for children exposed to a range of adversity and types of mental disorders. Dissemination and implementation science is crucial to establish how proven effective interventions could be scaled up and implemented in schools.

Identification, synthesis and characterization of an unknown process related impurity in eslicarbazepine acetate active pharmaceutical ingredient by LC/ESI-IT/MS, 1H, 13C and 1H-1H COSY NMR.

A new impurity was detected during high performance liquid chromatographic (HPLC) analysis of eslicarbazepine acetate active pharmaceutical ingredient. The structure of unknown impurity was postulated based on liquid chromatography mass spectrometry using electrospray ionization and ion trap analyzer (LC/ESI-IT/MS) analysis. Proposed structure of impurity was unambiguously confirmed by synthesis followed by characterization using 1H, 13C nuclear magnetic resonance spectrometry (NMR), 1H-1H correlation spectroscopy (COSY) and infrared spectroscopy (IR). Based on the spectroscopic and spectrometric data, unknown impurity was characterized as 5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl propionate.

Identification, synthesis and characterization of an unknown process related impurity in eslicarbazepine acetate active pharmaceutical ingredient by LC/ESI-IT/MS, 1H, 13C and 1H-1H COSY NMR / 药物分析学报

A new impurity was detected during high performance liquid chromatographic (HPLC) analysis of eslicarbazepine acetate active pharmaceutical ingredient. The structure of unknown impurity was postulated based on liquid chromatography mass spectrometry using electrospray ionization and ion trap analyzer (LC/ESI-IT/MS) analysis. Proposed structure of impurity was unambiguously confirmed by synthesis followed by characterization using 1H, 13C nuclear magnetic resonance spectrometry (NMR), 1H-1H correlation spectro-scopy (COSY) and infrared spectroscopy (IR). Based on the spectroscopic and spectrometric data, unknown impurity was characterized as 5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl propionate.

Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MS(n).

The present study describes the identification and characterization of two process impurities and major stress degradants in darifenacin hydrobromide using high performance liquid chromatography (HPLC) analysis. Forced degradation studies confirmed that the drug substance was stable under acidic, alkaline, aqueous hydrolysis, thermal and photolytic conditions and susceptible only to oxidative degradation. Impurities were identified using liquid chromatography coupled with ion trap mass spectrometry (LC-MS/MS(n)). Proposed structures were unambiguously confirmed by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and elemental analysis (EA). Based on the spectroscopic, spectrometric and elemental analysis data, the unknown impurities were characterized as 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxo-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-A), 2-[1-(2-benzofuran-5-yl-ethyl)-pyrrolidin-3-yl]-2,2-diphenylacetamide (Imp-B), 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-ethyl]-1-oxy-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-C) and 2-{1-[2-(7-bromo-2,3-dihydrobenzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-D). Plausible mechanisms for the formation and control of these impurities have also been proposed. The method was validated as per regulatory guidelines to demonstrate specificity, sensitivity, linearity, precision, accuracy and the stability-indicating nature. Regression analysis showed a correlation coefficient value greater than 0.99 for darifenacin hydrobromide and its impurities. The accuracy of the method was established based on the recovery obtained between 86.6 and 106.7% for all impurities.

4-[3,5-Bis(2-hy-droxy-phen-yl)-1H-1,2,4-triazol-1-yl]benzoic acid dimethyl-formamide monosolvate.

In the mol-ecule of deferasirox dimethyl-formamide solvate, C(21)H(15)N(3)O(4)·C(3)H(7)NO, the central 1,2,4-triazole ring is tilted with respect to the benzoic acid and one of the 2-hy-droxy-phenyl units but coplanar with the other 2-hy-droxy-phenyl group, as indicated by the dihedral angles of 33.69 (9), 72.57 (8) and 5.18 (9)°, respectively. Intra-molecular O-H⋯N hydrogen bonds generate an S(6) ring motif. In the crystal, deferasirox mol-ecules are linked by O-H⋯N hydrogen bonds and weak C-H⋯O inter-actions into chains along the c axis. The dimethyl-formamide solvent mol-ecules are located between the deferasirox chains and are linked to the deferasirox mol-ecules by O-H⋯O hydrogen bonds and weak C-H⋯O inter-actions.

Identification, characterization and quantification of a new impurity in deferasirox active pharmaceutical ingredient by LC-ESI-QT/MS/MS.

An unknown impurity was detected in deferasirox drug substance by a newly developed high performance liquid chromatography (HPLC) method. The unknown impurity was identified by liquid chromatography-tandem mass spectrometry using electrospray ionization source and Q-trap mass analyzer (LC-ESI-QT/MS/MS). Based on LC-MS/MS data and knowledge of the synthetic scheme of deferasirox, this impurity was proposed as the regio-isomer of deferasirox. Structural confirmation of this impurity was unambiguously carried out by synthesis followed by characterization using nuclear magnetic resonance (NMR), infrared spectroscopy (IR), mass spectrometry, elemental analysis (EA) and the impurity was confirmed as 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]-triazol-1-yl]-benzoic acid (Imp-1). The newly developed method was validated according to ICH guidelines. The resolution between Imp-1 and deferasirox was found to be more than 6.0 and the detection limit of impurities was in the range of 0.0005-0.01%, indicating high selectivity and sensitivity of the newly developed method.

A stability indicating simultaneous dual wavelength UV-HPLC method for the determination of potential impurities in fampridine active pharmaceutical ingredient.

A novel, sensitive, stability indicating simultaneous dual wavelength reverse phase UV-HPLC method has been developed for the quantitative determination of potential impurities of fampridine active pharmaceutical ingredient. Efficient chromatographic separation was achieved on a C18 stationary phase in gradient mode and quantitation by ultraviolet dual wavelength detection. The method was validated according to ICH guidelines with respect to specificity, precision, linearity and accuracy. Regression analysis showed correlation coefficient value greater than 0.999 for fampridine and its seven impurities. Detection limit as low as 0.003% was achieved for fampridine N-oxide and 0.01% for other impurities. Accuracy of the method was established based on the recovery obtained between 93.3% and 110.0% for all impurities. The method was found to be specific, selective to the degradation products and robust. Peak purity analysis by PDA detector confirmed the specificity of the method. Major degradation of the drug substance was found to occur under oxidative stress conditions to form fampridine N-oxide.

Highly efficient, selective, sensitive and stability indicating RP-HPLC-UV method for the quantitative determination of potential impurities and characterization of four novel impurities in eslicarbazepine acetate active pharmaceutical ingredient by LC/ESI-IT/MS/MS.

A novel, sensitive, selective and stability indicating LC-UV method was developed for the determination of potential impurities of eslicarbazepine acetate. High performance liquid chromatographic investigation of eslicarbazepine acetate laboratory sample revealed the presence of several impurities. Three impurities were characterized rapidly and four impurities were found to be unknown. The unknown impurities were identified by liquid chromatography coupled with electrospray ionization, ion trap mass spectrometry (LC/ESI-IT/MS/MS). Structural confirmation of these impurities was unambiguously carried out by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (FT-IR) and mass spectrometry (MS). Based on the spectroscopic, spectrometric and elemental analysis data unknown impurities were characterized as 5-acetyl-5,11-dihydro-10H-dibenzo [b,f]azepin-10-one, N-acetyl-5H-dibenzo[b,f]azepine-5-carboxamide, 5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl acetate and 5-acetyl-5H-dibenzo[b,f]azepin-10-yl acetate. The newly developed LC-UV method was validated according to ICH guidelines considering eleven potential impurities and four new impurities to demonstrate specificity, precision, linearity, accuracy and stability indicating nature of the method. The newly developed method was found to be highly efficient, selective, sensitive and stability indicating. A plausible pathway for the formation of four new impurities is proposed.

Quantification of potential impurities by a stability indicating UV-HPLC method in niacinamide active pharmaceutical ingredient.

A sensitive, stability indicating reverse phase UV-HPLC method has been developed for the quantitative determination of potential impurities of niacinamide active pharmaceutical ingredient. Efficient chromatographic separation was achieved on C18 stationary phase in isocratic mode using simple mobile phase. Forced degradation study confirmed that the newly developed method was specific and selective to the degradation products. Major degradation of the drug substance was found to occur under oxidative stress conditions to form niacinamide N-oxide. The method was validated according to ICH guidelines with respect to specificity, precision, linearity and accuracy. Regression analysis showed correlation coefficient value greater than 0.999 for niacinamide and its six impurities. Detection limit of impurities was in the range of 0.003-0.005% indicating the high sensitivity of the newly developed method. Accuracy of the method was established based on the recovery obtained between 93.3% and 113.3% for all impurities.

Identification, characterization and quantification of new impurities by LC-ESI/MS/MS and LC-UV methods in rivastigmine tartrate active pharmaceutical ingredient.

Six impurities were detected at trace level in rivastigmine tartrate drug substance by a newly developed high performance liquid chromatography method. Three impurities were characterized rapidly and three impurities were found to be unknown. The unknown impurities were enriched and identified with a combination of semi-preparative HPLC and LC/MS/MS techniques. Proposed structures were further confirmed by characterization using NMR, FT-IR, and EA techniques of impurity standards. Based on the spectroscopic, spectrometric and elemental analysis data unknown impurities were characterized as 3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methyl carbamate N-oxide, ethyl-methyl-carbamic acid 4-(1-dimethylamino-ethyl)-phenyl ester and ethyl-methyl-carbamic acid 2-(1-dimethylamino-ethyl)-phenyl ester. A plausible mechanism for the formation of these impurities is also proposed. The method was validated according to ICH guidelines for fourteen impurities to demonstrate specificity, precision, linearity, accuracy and stability indicating nature of the method. Regression analysis showed correlation coefficient value greater than 0.999 for rivastigmine tartrate and its impurities. Accuracy of the method was established based on the recovery obtained between 93.41 and 113.33% for all impurities.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Identification and structural elucidation of an unknown impurity in carbamazepine active pharmaceutical ingredient by liquid chromatography-tandem mass spectrometry and semi-preparative chromatographic isolation.

Two impurities were detected in the HPLC analysis of crude carbamazepine active pharmaceutical ingredient. One of the impurities of the order of 0.5% was found to be unknown and has not been reported previously. A LC-MS compatible reverse phase isocratic method was developed and tandem mass spectrometry was performed using electrospray ionization source and ion trap mass analyzer. Isolation of unknown impurity was performed by semi-preparative HPLC followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (FT-IR) and elemental analysis (CHNS) confirmed its structure as tetrabenzo[b,f,b'f']azepino[4',5':4,5]thieno[2,3-d]azepine-3,9-dicarboxamide. A plausible mechanism for the formation of this impurity is proposed.

Paliperidone: 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]eth-yl}-9-hy-droxy-2-methyl-1,6,7,8,9,9a-hexa-hydro-pyrido[1,2-a]pyrimidin-4-one.

The title compound (also known as 9-hy-droxy-risperidone), C(23)H(27)FN(4)O(3), is a heterocyclic compound with manifold pharmacological properties. The hy-droxy group shows disorder over two positions, with site-occupancy factors of 0.856 (2) and 0.144 (2). The piperidine ring adopts a chair conformation, while the annulated ring bearing the hy-droxy group is present in a half-chair conformation. Classical O-H⋯O hydrogen bonds as well as C-H⋯N contacts connect the mol-ecules into undulating sheets lying perpendicular to the crystallographic b axis. The shortest centroid-centroid distance between two centers of gravity is 3.5867 (8) Šand is apparent between the benzoxazole moiety and the six-membered ring bearing the keto substituent.

The science of USP 1 and 2 dissolution: present challenges and future relevance.

Since its inception, the dissolution test has come under increasing levels of scrutiny regarding its relevance, especially to the correlation of results to levels of drug in blood. The technique is discussed, limited to solid oral dosage forms, beginning with the scientific origins of the dissolution test, followed by a discussion of the roles of dissolution in product development, consistent batch manufacture (QC release), and stability testing. The ultimate role of dissolution testing, "to have the results correlated to in vivo results or in vivo in vitro correlation," is reviewed. The recent debate on mechanical calibration versus performance testing using USP calibrator tablets is presented, followed by a discussion of variability and hydrodynamics of USP Apparatus 1 and Apparatus 2. Finally, the future of dissolution testing is discussed in terms of new initiatives in the industry such as quality by design (QbD), process analytical technology (PAT), and design of experiments (DOE).