Choice of Methodology Impacts Outcome in Indirect Comparisons of Drugs for Idiopathic Pulmonary Fibrosis.

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a chronic condition leading to lung damage and deterioration in lung function. Following the availability of two new drugs, nintedanib and pirfenidone, a number of network meta-analyses (NMAs) of randomised controlled trials have been published which have conducted indirect comparisons on the two drugs. Differing recommendations from these studies are potentially confusing to clinicians and decision-makers. We aimed to systematically review published NMAs of IPF treatments, to compare their findings and summarise key recommendations. Materials and Methods: We systematically reviewed (PROSPERO: CRD42017072876) six eligible NMAs and investigated the differences in their findings with respect to key endpoints. We focused on differences in head-to-head comparisons between nintedanib and pirfenidone. Results: The NMAs were broadly consistent, with most differences being explained by model choice, endpoint definitions, inclusion of different studies, different follow-up durations, and access to unpublished data. A substantive difference remained, however, in the change from baseline forced vital capacity (FVC). One NMA favoured nintedanib, another found no statistical difference, whilst others did not conduct the analysis. These differences can be attributed to the choice of methodology, the use of the standardised mean difference (SMD) scale, and population heterogeneity. Conclusions: NMA methods facilitated the comparison of nintedanib and pirfenidone in the absence of a head-to-head trial. However, further work is needed to determine whether the trial populations are homogeneous and whether the SMD is appropriate in this population. Differences in patient characteristics may obscure the difference in treatment effects. To assist decision-makers, an exploration of efficacy in real-world populations may be prudent.

XLR-11 and UR-144 in Washington state and state of Alaska driving cases.

The case reports for 18 driving cases positive for the synthetic cannabinoid substances XLR-11 and/or UR-144 are discussed. Eleven of these cases had drug recognition expert evaluations performed. Slurred speech, lack of convergence and body and eyelid tremors were the most consistently noted interview characteristic. Pulse and blood pressure of the subjects were within the expected range. Most of the drivers contacted demonstrated poor driving; however, their performance on the standardized field sobriety tests yielded inconsistent diagnostic information. All cases were negative for other commonly detected drugs that affect the central nervous system, although one case was additionally positive for other synthetic cannabinoids. Of the studied cases, six were positive for only UR-144, whereas eight contained only XLR-11. Four cases were found to have both.

Feasibility studies. The use of NMR spectrometry as a possible substitute of or complement to several analytical tests in pharmacopoeia monographs.

NMR spectrometry has many analytical applications; for instance, the identification of known substances; the structure elucidation of unknown ones; the quantification of APIs, impurities, solvent and water; kinetic studies, stereochemistry determinations, and the analyses of complex mixtures as in metabonomics. NMR spectrometry has the potential to substitute or complement existing analyses that are performed on APIs. In this work, 4 different NMR analyses were done on 2 APIs: fluvastatin sodium and benzalkonium chloride with good results.

Direct identification of dyes in textiles by direct analysis in real time-time of flight mass spectrometry.

We present here a method requiring no sample preparation for direct identification of the organic dye compounds quercetin, indigotin, and alizarin in reference materials, in solution, and also in situ in dyed fibers by use of direct analysis in real time (DART) ionization and high-resolution time-of-flight mass spectrometry. Exact mass determinations on small samples of dyed textiles were completed in less than 1 min. With the ability to identify flavonoid, indigoid, and anthraquinone classes of dyes, this technique shows early promise as an additional analytical tool in the challenging analysis of organic dyes in rare cultural heritage materials and possesses the unique advantages of sensitivity and simplicity without the preparatory procedures required by other methods.

Determination of tegaserod by LC-ESI-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.

A simple, rapid and sensitive high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) assay for determination of tegaserod in human plasma using diazepam as internal standard (IS) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C18 column with a mobile phase of methanol: 5 mM ammonium acetate (75:25, v/v, adjusting the pH to 3.5 with glacial acetic acid). The quantification of target compounds was obtained by using multiple reaction monitoring (MRM) transitions; m/z 302.5, 173.2 and 285.4, 193.2 were measured in positive mode for tegaserod and internal standard (diazepam), respectively. The lower limit of quantification (LLOQ) was 0.05 ng/ml. The calibration curves were linear over the range 0.05-8.0 ng/ml (r=0.9996) for tegaserod. The mean absolute recovery of tegaserod was more than 85.56%. Intra- and inter-day variability values were less than 9.21% and 10.02%, respectively. The samples were stable for 8h under room temperature (25 degrees C, three freeze-thaw cycles in 30 days and for 30 days under -70 degrees C). After administration of a single dose of tegaserod maleate 4 mg, 6 mg and 12 mg, respectively, the area under the plasma concentration versus time curve from time 0 h to 12 h (AUC0-12) were (2.89+/-0.88), (5.32+/-1.21) and (9.38+/-3.42) ng h/ml, respectively; peak plasma concentration (Cmax) were (1.25+/-0.53), (2.21+/-0.52) and (4.34+/-1.66) ng/ml, respectively; apparent volume of distribution (Vd/F) were (6630.5+/-2057.8), (7615.2+/-2242.8) and (7163.7+/-2057.2) l, respectively; clearance rate (CL/F) were (1851.4+/-496.9), (1596.2+/-378.5) and (1894.2+/-459.3) l/h, respectively; time to Cmax (Tmax) were (1.00+/-0.21), (1.05+/-0.28) and (1.04+/-0.16) h, respectively; and elimination half-life (t1/2) were (3.11+/-0.78), (3.93+/-0.92) and (3.47+/-0.53) h, respectively; MRT were (3.74+/-0.85), (4.04+/-0.56) and (3.28+/-0.66) h, respectively. The essential pharmacokinetic parameters after oral multiple doses (6mg, b.i.d) were as follows: Cssmax, (2.72+/-0.61) ng/ml; Tmax, (1.10+/-0.25) h; Cssmin, (0.085+/-0.01) ng/ml; Cav, (0.54+/-0.12) ng/ml; DF, (4.84+/-0.86); AUCss, (6.53+/-1.5) ngh/ml. This developed and validated assay method had been successfully applied to a pharmacokinetic study after oral administration of tegaserod maleate in healthy Chinese volunteers at a single dose of 4 mg, 6 mg and 12 mg, respectively. The pharmacokinetic parameters can provide some information for clinical medication.

Isolation and identification of a major impurity in a new bulk drug candidate by preparative LC, ESI-MS(n), LC-MS-MS, and NMR.

A simple preparative liquid chromatography (LC) method is developed to isolate a major impurity in a new bulk drug candidate, 6-bromo-4-(carbamidinemethyl)-5-hydroxy-1-methyl-2-(phenylthiomethyl)-1H-indole-3-carboxylic acid ethyl ester hydrochloride monohydrate (carmidole). The carmidole solution for preparation is exposed to daylight before isolation. Based on the electrospray ionization (ESI)-mass spectroscopy (MS(n)) spectral data of the impurity fraction and carmidole, the impurity is preliminarily characterized as 6-bromo-4-(carbamidinemethyl)-5-hydroxy-1-methyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester. LC-MS-MS is used to analyze a carmidole sample. The impurity, lyophilate, is obtained from the fraction of preparative LC, and the impurity standard is synthesized. By comparison of the retention times of high-performance liquid chromatography, ESI-MS(n), and (1)H-nuclear magnetic resonance of the impurity lyophilate with impurity standard and carmidole itself, the structure of the impurity is confirmed and its formation is discussed.

Simultaneous determination of Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (SU5416) and its interconvertible geometric isomer (SU5886) in rat plasma by LC/MS/MS.

Z-3-[(2,4-Dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (SU5416) is a cytostatic substance in development as an anti-angiogenic agent. SU5416 exists as the thermodynamically stable cis or Z-isomer as a solid. Studies have shown that in light exposed solutions of SU5416, the unstable trans or E-isomer, namely SU5886, is formed. The E-isomer converts back to the Z-isomer when protected from light. The E-isomer is unstable for synthesis and isolation; therefore, the analytical standard of the E-isomer is not available. In this study, a simple, fast and reliable LC/MS/MS method has been developed to determinate both isomers simultaneously in rat plasma samples to support the study of disposition kinetics of SU5416. This method is sensitive (limit of quantitation (LOQ=0.5 ng/mL)), reproducible and has a wide linear range (0.5-2500 ng/mL). There was no conversion between E- and Z-isomer during sample preparation procedure and sample determination with LC/MS/MS. Experimental results proved that SU5416 and SU5886 have identical detection response. Therefore, SU5416 (Z-isomer) was used successfully as analytical standard for SU5886 (E-isomer). This method has been applied to rat plasma samples obtained from a pharmacokinetic study. This study underscores the use of LC/MS/MS technique for bioanalytical methods where analytical standards are not available and analytes are interconvertible.

Detection and quantification of 5-hydroxyoxindole in mammalian sera and tissues by high performance liquid chromatography with multi-electrode electrochemical detection.

OBJECTIVE: Since 5-hydroxyoxindole structurally related indole metabolites play different roles in some hepatic and neurologic disorders we found necessary to develop an assay to further investigate the physiologic relevance of this compound. METHODS: We have designed a convenient assay to determine 5-hydroxyoxindole in serum using solid phase extraction and a highly selective High Performance Liquid Chromatography system with multi-Electro Chemical Detection (HPLC-ECD). RESULTS: We have identified and quantified 5-hydroxyoxindole in various mammalian species. Its distribution in tissues showed that the molecule is also present in brain, liver, kidney and spleen, but not in skeletal muscle. CONCLUSIONS: 5-hydroxyoxindole is an endogenous tryptophan metabolite present in circulating blood and in some tissues at the nmol level, its determination using HPLC-ECD will be useful for elucidating the role of this molecule in normal and disease conditions.

Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation.

Estrogens are represented by a diverse group of compounds. Within this large family of molecules are tissue-selective estrogens that have been classified as selective estrogen receptor modulators (SERMs). These compounds are characterized by the fact that they exhibit both estrogen agonist and antagonist activity dependent upon the gene promoter and target tissue being examined. SERMs have been intensively studied over the past decade, especially since one, raloxifene, has been approved for the prevention and treatment of postmenopausal osteoporosis. While not a replacement for hormone replacement therapy (HRT), raloxifene can be an alternative to it and other treatments for osteoporosis. The ideal SERM would provide the positive benefits associated with HRT without the uterine and breast stimulation. Raloxifene does achieve some of the benefits of HRT, specifically on the skeleton and lipid metabolism with no apparent uterine effects, and a potential decreased risk of developing breast cancer associated with raloxifene therapy. However, there are a number of parameters that can be improved. A number of SERMs have been evaluated only to fail in development due to, for the most part, uterine safety issues. In order to develop an improved SERM, a stringent screening process was designed to select compounds that did not stimulate the uterus or breast. At the same time, these new compounds would have a positive impact on the skeleton and lipid metabolism with the additional improvement (over raloxifene) of a neutral effect on hot flashes. Under these strict conditions, WAY-140424 was developed and, to date, the preclinical pharmacology data have accurately predicted the clinical response demonstrated in phase I and II trials.

From sugar beet molasses to Lyphan. Integrated quality management from the raw material to the drug.

L-tryptophan is produced at the AMINO GmbH (Frellstedt, FRG) via biocatalytical condensation of the amino acid L-serine with indole. As a biocatalyst, tryptophan synthetase is used which is produced in high activities by a natural mutant Escherichia coli strain. The enzyme mechanism and specificity and the individual process-parameters for the biotransformation procedure are explained as well as the purification process of educts and products. This includes a detailed description of the quality control of educts, intermediates and final product. The active ingredient L-tryptophan is subsequently used by AMINO's subsidiary company esparma GmbH to produce and distribute the pharmaceutical Lyphan. The quality management system and the production procedure for Lyphan are described and discussed.

[Comparison on the quality of scolopendra commodities from different gathering periods].

Through physo-chemical analysis and pharmacological study to Scolopendra commodites, it showed that the quality of the commodities from autumn was better but gather, dry and store difficultly. According to market, gathering at Spring is available.

Perindopril plus nifedipine versus perindopril plus hydrochlorothiazide in mild to severe hypertension: a double-blind multicentre study. The Multicentre Study Group on Treatment Association with Perindopril.

Thiazide diuretics are considered as the choice drug to combine with ACE inhibitors for the treatment of hypertension. However, there is much evidence showing that the combination of ACE inhibitors with a calcium channel blocker is effective and safe. We compared the safety and efficacy of perindopril 8 mg once daily plus nifedipine SR 10 mg twice daily with perindopril 8 mg once daily plus hydrochlorothiazide (HCTZ) 12.5 mg once daily in a two phase three month study. After a one month placebo run-in period, patients whose DBP averaged 95-125 mmHg received perindopril 4 mg once daily for the first open phase (n = 524). After one month those whose DBP remained > 90 mmHg were prescribed perindopril 8 mg once daily for a second month. Among them, those whose DBP were still > 90 mmHg entered the second phase for one month, in a double-blind fashion. Fifty-three patients received HCTZ (BP: 161.2/99.2 +/- 2.0/0.9 mmHg), 57 received nifedipine (BP: 161.4/98.7 +/- 2.2/0.7 mmHg). Five patients withdrew due to side-effects, three patients in the perindopril plus nifedipine group and two in the perindopril plus HCTZ group. After one month there was a significant drop in BP (P < 0.01) in both groups: perindopril plus HCTZ (-13.9/-11.9 mmHg) and perindopril plus nifedipine (-12.1/-10.8 mmHg). Heart rate was not significantly modified: perindopril plus HCTZ (-1.30 beats/min), perindopril plus nifedipine (+0.54 beats/min). There were no significant difference between the two combinations for BP reduction and heart rate. The incidence of adverse experiences was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of fluvastatin in hypertensive patients. An analysis of a clinical trial database.

The concurrence of hypertension and hypercholesterolemia leads to the clinical need to lower lipids in hypertensive patients. Thus, it is interesting to evaluate the efficacy and safety of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in such a patient population. A retrospective analysis of the clinical efficacy and safety of fluvastatin was based on the data from 1815 patients who received fluvastatin at daily doses of > or = 20 mg compared with 783 patients taking placebo. The results showed that 332 (18.3%) of the fluvastatin-treated and 124 (15.8%) of the placebo-treated patients were identified as having hypertension. The percentage change from baseline of low-density lipoprotein cholesterol (LDL-C) in hypertensive patients taking fluvastatin at doses of 20 and 40 mg/day was -20% and -26%, respectively (placebo: 1.4%), and did not differ from the response in non-hypertensive patients. Increases in high-density lipoprotein cholesterol (HDL-C) as well as decreases in triglycerides with fluvastatin were not consistently different between hypertensive and non-hypertensive patients. Irrespective of the presence or absence of hypertension, confirmed (measured on two consecutive occasions) increases > three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) were observed in three (0.2%) and 12 (0.7%) patients, respectively. With placebo, ALAT was increased in two patients (0.2%). The incidence of notable increases more than 10 times the upper limit of normal in creatine kinase was similar with fluvastatin compared with placebo (0.3% in both).(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and tolerability of fluvastatin with concomitant use of antihypertensive agents. An analysis of a clinical trial database.

The coexistence of hypercholesterolemia and hypertension often requires concomitant drug treatments. Thus, it is interesting to evaluate the efficacy, safety, and tolerability of the new lipid-lowering agent fluvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in patients receiving concomitant antihypertensive/cardiovascular drug treatments. A retrospective analysis was based on data from controlled clinical trials in which 1815 patients were treated with fluvastatin and 783 patients received placebo. The daily dose of fluvastatin was > or = 20 mg. At least one of the following drug treatments was taken by 445 of the fluvastatin-treated patients (24.5%) and 181 of those receiving placebo (23.1%): beta-adrenergic-receptor blockers (fluvastatin: n = 182; placebo: n = 84); diuretics (fluvastatin: n = 168; placebo: n = 72); calcium antagonists (fluvastatin: n = 161; placebo: n = 69); and angiotensin-converting enzyme (ACE) inhibitors (fluvastatin: n = 101; placebo: n = 30). The majority of patients received monotherapy with one of the above-mentioned antihypertensive agents (fluvastatin: 69%; placebo: 65%). The efficacy of fluvastatin in modifying low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol and triglyceride levels was not consistently different in patients taking a given antihypertensive compared with the overall group and the patients not taking the antihypertensive agent. In patients taking fluvastatin and antihypertensives, confirmed (measured at two consecutive occasions) increases more than three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) occurred in only two patients. One case involved the concomitant use of a beta-blocker (ASAT and ALAT) and the other a diuretic (ALAT).(ABSTRACT TRUNCATED AT 250 WORDS)

Improved preparation and structural elucidation of the tryptophan cleavage reagent 2-(2'-nitro-phenylsulfenyl)-3-methyl-3-bromoindolenine (BNPS-skatole).

Methods are described for a high yield preparation (overall yield greater than 90%) of analytically pure 2-(2'-nitrophenylsulfenyl)-3-methyl-3-bromoindolenine (BNPS-skatole). The chromatographic and spectroscopic data are given. The yield of tryptophan cleavage is considerably dependent on the degree of purity of the BNPS-skatole.