Supercritical Fluid Chromatography—Mass Spectrometry (SFC-MS) and MALDI-TOF-MS of Heterocyclic Compounds with Trivalent and Pentavalent Nitrogen in Cough Relief Medical Forms Tuxi and Cosylan

Alkaloids are natural, semisynthetic or synthetic organic compounds, normally polar with basic chemical properties and containing at least one nitrogen atom in a heterocyclic ring. Some synthetic or semisynthetic substances resemble the alkaloid architecture. Trivalent nitrogen in these substances is normal;however, some natural and semisynthetic alkaloids have pentavalent nitrogen. The drug pholcodine is a derivative of morphine. Pholcodine has very little addiction- developing effect. It is a semisynthetic alkaloid that was first synthesized in 1950 by Chabrier et al. Pholcodine possesses antitussive (cough relief) properties similar to codeine, morphine and ethylmorphine. The drug was used in liquid formulations as Tuxi and Tuxi Forte, and it is in present use in Tuxidrin as liquid mixture and in tablet form. Pholcodine is an Active Pharmacological Ingredient (API) in tablets and liquid mixtures. Leiras International and Weifa in Norway manufacture medical forms with pholcodine. Several impurities in pholcodine were described by J. Roe in 1997 and by Denk et al. in 2000 and 2002. In addition, several degradation products may be formed in liquid formulations under storage. Some of these products are related not to the original production of pholcodine but rather to its oxidation under storage. The appearance of degradation products strongly depends on the storage temperature and pH of the liquid phase. Pholcodine-N-oxide and pholcodine-N,N’-dioxide are among the degradation (oxidation) products;pholcodine can also degrade to morphine. There is little information about the toxicity of the N-oxide and no information on the N,N’-di- oxide of pholcodine. In this study, the fact that morphine is generated during the storage of formulations containing pholcodine is presented. Another antitussive mixture under the name Cosylan was analyzed to examine the oxidation of ethylmorphine to ethylmorphine-N-oxide. Ethylmorphine is the API in Cosylan.

Mass Spectrometric Structure Elucidation of the Trivalent and Pentavalent Nitrogen Contaminants of Pholcodine in the Cough Relief Medical Form Tuxidrin

In the paper “Supercritical Fluid Chromatography-Mass Spectrometry (SFC-MS) and MALDI-TOF-MS of Heterocyclic Compounds with Trivalent and Pentavalent Nitrogen in Cough Relief Medical Forms Tuxi and Cosylan” [1], the presence of morphine and other degradation products of pholcodine in cough relief medical forms of Tuxi are discussed. Tuxiis recalled from the Norwegian market by Weifa pharmaceutical company, and hence it no longer presents problems to users and health authorities there;however, the medical form Tuxidrin, which contains a significant amount of pholcodine as the active pharmacological ingredient, is still marketed. In the present paper, Tuxidrin is analyzed to determine the presence of degradation products of pholcodine. The degradation of pholcodine to morphine has been discussed previously as a factor in the development of addiction to narcotics in young persons. The structures of the contaminants in Tuxidrin, such as oxides of pholcodine, are elucidated in the present paper. The toxicity and pharmacology of oxides of alkaloids have generally not been well studied, and very little is known about the toxicity and pharmacology of the degradation (oxidation) products of pholcodine: the N-oxide and the N, N'-dioxide of pholcodine. According to Brondz and Brondz[1], the N-oxide and possibly also the N, N'-dioxide are less toxic than the original alkaloids and possess greater pharmacological activity, and hence they may be a source of useful new semisynthetic drugs. The question of possible addiction to pholcodine oxides has not been studied, and the potential of these substances to provoke allergies is unclear. The recall of Tuxi from the Norwegian marketis mainly based on the fact that pholcodine causes significantly increased levels of IgE antibodies in sensitized patients. Tuxidrin contains pholcodine and has the same negative effect as Tuxi, namely provoking allergies or even anaphylactic shock. From this point of view, Tuxidrin has no advantage over Tuxi. These two medical forms only differ in one respect: Tuxidrin requires a prescription (prescription duty medicine), but Tuxi doesnot (prescription free medicine). This aspect is also discussed in the present paper.

Tetanus Toxin Antibody Levels in Pre-School Nigerian Children after Three Doses of Diphtheria-Pertussis-Tetanus/Pentavalent Immunization: A Cross-Sectional Study

Background: Post-neonatal tetanus is an important problem. Prevention of tetanus in Nigeria is via immunization with three doses of Diphtheria-Pertussis-Tetanus (DPT)/Pentavalent vaccine at 6, 10 and 14 weeks. The anti-tetanus antibody levels of these children are not known after they had received DPT3/Pentavalent vaccines. Aim: This work was to determine the anti-tetanus antibody (IgG) response in Nigerian children aged six months to five years who had received three doses of DPT vaccine in early infancy. Methods: Children aged six months to five years who were attended to in the University of Calabar Teaching Hospital for acute illnesses were recruited. Their anti-tetanus IgG levels were measured using Enzyme Linked Immunosorbent Assay (ELISA). The optimal cut-off level of ≥0.1 IU/ml was used as the protective level. Data was analysed using the Statistical Package for Social Sciences (SPSS) version 20.0 with simple proportions and percentages. Students’ “t” test and ANOVA were used to compare quantitative variables while Chi-square and Fisher’s exact test were used to compare categorical data. Results: Four hundred and eighteen children participated in the study. The mean IgG antibody level was 1.021 ± 0.9 IU/ml. Four hundred children (95.7%) had protective levels of antibodies. The highest proportion of subjects with protective levels was in infants, 6 - 11 months (99%) and lowest in children aged 36 - 47 months (92.2%). Conclusion: The proportion of children with protective levels was above 90% in all age groups studied. The current national immunization schedule is adequate. Further studies in older age groups are needful.

Comparative Pertussis Antibody Response of Nigerian Children to Diphtheria, Pertussis, Tetanus (DPT) and Pentavalent Vaccines

Background: In Nigeria Pentavalent vaccine had replaced Diphtheria-Pertussis- Tetanus [DPT] vaccine in the prevention of pertussis since 2012. Aims and Objectives: The aim of this study was to compare the anti-pertussis immunoglobin G (IgG) response of children who received DPT with those who received the pentavalent vaccine. Subjects and Methods: This study was carried out in Akpabuyo LGA of Cross River State from April to June 2016. It was a cross-sectional survey of anti-pertussis IgG levels in children aged 6 months to 5 years who received DPT and those who received pentavalent vaccine. IgG antibody levels were determined using enzyme-linked immunosorbent assay. The protective level was set at >11 DU according to manufacturer’s cut off point. Results: Seventy eight out of 230 children [33.9%] who had received DPT had protective levels of anti-pertussis IgG compared to 74 out of 192 children [38.5%] who had received pentavalent vaccine. The difference was not statistically significant [p = 0.61]. The median IgG antibody level in those who received DPT was 8.0 DU (interquartile range (IQR) 4.0 - 13.0) compared with 9.0 DU (IQR) 4.0 - 15.0 in those who received pentavalent vaccine [p = 0.18]. No single factor investigated predicted the development of protective levels of antibody in the multivariate analysis. Conclusion/Recommendation: There was no difference in the antipertussis antibody response between DPT and pentavalent vaccines recipients. Further study is needed to elucidate factors that could be responsible for low anti-pertussis antibody response in this population.

One-Electron-Addition to Pentavalent Phosphorus with the Phosphorus-Chlorine Bond as Acceptor Introducing a Fundamental Distinction in Substitution Mechanism between S_N2(P) and S_N2(C)

An electron-addition, under single-crystal conditions, to pentavalent phosphorus compounds as Cl-P (=O, S) Y, Z with the P-Cl bond as electron-accepting group, is selected as an additional model for SN2(P) like reactions. It is demonstrated that the geometric information stored in the tetrahedral configuration (substrate) can be transmitted in the corresponding trigonal bipyramidal (TBP) state for nucleophilic substitution. In this article, we focus on these specific mechanistic aspects of carbon and phosphorus. We consider our study as a contribution to the significance of these (bio)chemical intermediates.

Prevalence and factors associated with pentavalent vaccination:a cross-sectional study in Southern China

Background Immunization is one of the most far-reaching and cost-effective strategies for promoting good health and saving lives.A complex immunization schedule,however,may be burdensome to parents and lead to reduced vaccine compliance and completion.Thus,it is critical to develop combination vaccines to reduce the number of injections and simplify the immunization schedule.This study aimed to investigate the current status of the pentavalent diphtheria-tetanus-acellular pertussis inactivated poliomyelitis andHaemophilus influenzae type B conjugate(DTaP-IPV/Hib)vaccination in Southern China as well as explore the factors in the general population associated with uptake and the differences between urban and rural populations.Methods A cross-sectional study was conducted with recently enrolled kindergarten students in Hainan Province between December 2022 and January 2023.The study employed a stratified multistage cluster random sampling method.Information regarding the demographic characteristics and factors that influence decisions were collected from the caregivers of children via an online questionnaire.Multivariate logistic regression was used to determine the factors associated with the status of DTap-IPV/Hib vaccinations.Results Of the 4818 valid responses,95.3%of children were aged 3-4 years,and 2856(59.3%)held ruralhukou.Coverage rates of the DTaP-IPV/Hib vaccine,from 1 to 4 doses,were 24.4%,20.7%,18.5%,and 16.0%,respectively.Caregivers who are concerned about vaccine efficacy[adjusted odds ratio(aOR)=1.53,95%confidence interval(CI):1.30-1.79],the manufacturer(aOR=2.05,95%CI:1.69-2.49),and a simple immunization schedule(aOR=1.26,95%CI:1.04-1.54)are factors associated with a higher likelihood of vaccinating children against DTaP-IPV/Hib.In addition,caregivers in urban areas showed more concern about the vaccine price(P=0.010)and immunization schedule(P=0.022)in regard to vaccinating children.Conclusions The DTaP-IPV/Hib vaccine coverage rate in Hainan Province remains low.Factors such as lower socioeconomic status,cultural beliefs,concerns about vaccine safety,and cost may hinder caregivers from vaccinating their children.Further measures,such as health education campaigns to raise knowledge and awareness,and encouragement of domestic vaccine innovation,which would reduce out-of-pocket costs,could be implemented to improve the coverage of DTap-IPV/Hib vaccination.

Increased PIT1 and PIT2 Expression in Streptozotocin (STZ)-induced Diabetic Mice Contributes to Uptake of iAs^((V))

Objective This study aimed to investigate the susceptibility of mice with streptozotocin（STZ）-induced diabetes mellitus（TIDM） to the uptake of pentavalent inorganic arsenic（iAs^V） and the possible molecular mechanism. Methods TIDM was induced in mice by STZ. TIDM and normal mice were treated with 15.0 mg/kg Na2HAsO4·12H2O by intragastric administration. Then, the concentrations of arsenic in various tissues were measured by atomic fluorescence spectrometry. The gene expression levels of Pit1 and Pit2 were quantified by real-time RT-PCR, and their protein levels were detected by Western blotting in mouse heart, kidney, and liver tissues. Results The concentrations of arsenic in STZ-induced TIDM mouse tissues were higher at 2 h after intragastric administration of Na2HAsO4·12H2O. Compared with the levels in normal mice, PIT1 and PIT2, which play a role in the uptake of iAs^V, were upregulated in the livers and hearts of TIDM mice. PIT1 but not PIT2 was higher in TIDM mouse kidneys. The upregulation of Pit1 and Pit2 expression could be reversed by insulin treatment. Conclusion The increased uptake of iAs^V in TIDM mouse tissues may be associated with increased PIT1 and/or PIT2 expression.

Methylated and thiolated arsenic species for environmental and health research——A review on synthesis and characterization

Hundreds of millions of people around the world are exposed to elevated concentrations of inorganic and organic arsenic compounds, increasing the risk of a wide range of health effects. Studies of the environmental fate and human health effects of arsenic require authentic arsenic compounds. We summarize here the synthesis and characterization of more than a dozen methylated and thiolated arsenic compounds that are not commercially available. We discuss the methods of synthesis for the following14 trivalent（Ⅲ） and pentavalent（） arsenic compounds： monomethylarsonous acid（MMA~Ⅲ）, dicysteinylmethyldithioarsenite（MMA~Ⅲ（Cys）_2）, monomethylarsonic acid（MMA~Ⅴ）,monomethylmonothioarsonic acid（MMMTAⅤ） or monothio-MMA~Ⅴ, monomethyldithioarsonic acid（MMDTA~Ⅴ） or dithio-MMA~Ⅴ, monomethyltrithioarsonate（MMTTA~Ⅴ） or trithio-MMA~Ⅴ,dimethylarsinous acid（DMA~Ⅲ）, dimethylarsino-glutathione（DMA~Ⅲ（SG））, dimethylarsinic acid（DMA~Ⅴ）, dimethylmonothioarsinic acid（DMMTA~Ⅴ） or monothio-DMAⅤ, dimethyldithioarsinic acid（DMDTA~Ⅴ） or dithio-DMA~Ⅴ, trimethylarsine oxide（TMAO~Ⅴ）, arsenobetaine（AsB）, and an arsenicin-A model compound. We have reviewed and compared the available methods,synthesized the arsenic compounds in our laboratories, and provided characterization information. On the basis of reaction yield, ease of synthesis and purification of product, safety considerations, and our experience, we recommend a method for the synthesis of each of these arsenic compounds.

Stabilization of Plutonium(V)Within a Crown Ether Inclusion Complex

Crystalline coordination complexes of actinides,especially in atypical oxidation states,are not only fundamentally important for expanding the notably limited knowledge on the bonding nature of actinides but could also provide critical information toward the development of nuclear fuel cycle,waste management,and national security.Plutonium(Pu)is the only element in the periodic table that could exist in four oxidation states in aqueous solutions simultaneously.