S-Carboxymethyl-l-cysteine: a multiple dosing study using pharmacokinetic modelling.

S-Carboxymethyl-l-cysteine is a mucolytic agent used as adjunctive therapy in the treatment of respiratory disorders. Various mechanisms of action have been proposed but few studies have attempted to link the required in vitro concentrations with those achieved actually in vivo during clinical therapy.The data from several published studies has been re-analysed by WinNonlin using non-compartmental analysis modelling, Phoenix modelling and Classic PK compartmental modelling for both single (500-1500 mg) and multiple oral administration of the drug.Multiple dose modelling indicated maximum peak concentrations (Cmax) ranging from 1.29 to 11.22 µg/ml and those at steady state (Css(av)) from 1.30 to 8.40 µg/ml. For the standard therapeutic regimen of 3 × 750 mg (2250 mg/day) these values were 1.29-5.22 µg/ml (Cmax) and 1.30-3.50 µg/ml (Css(av)). No accumulation was observed.Hence, only the pharmacodynamic studies reporting significant effects below c.10 µg/ml were likely to occur in vivo and these were mainly gene-related mechanisms. The majority of events, although demonstrable in vitro, required levels much greater than possible to achieve in the clinical situation.Such unappreciated disregard for in vitro-in vivo 'concentration matching' may lead to erroneous conclusions regarding mechanisms of action for many drugs as well as for S-carboxymethyl-l-cysteine.

N-acetyltransferase: the practical consequences of polymorphic activity in man.

Over the years, numerous studies have supported the premise that individuals possessing the "slow acetylator" phenotype are more at risk from developing drug side-effects. Most prominent amongst these reports are those concerned with hepatotoxicity and peripheral neuropathy following treatment with isoniazid, lupus-like symptoms during procainamide therapy and experiencing hypersensitivity reactions to the various sulphonamide derivatives. Similarly, "slow acetylators" undergoing heavy exposure to arylamines and related carcinogens are more likely to develop bladder cancer. Contrariwise, there appears a slight risk of "rapid acetylators" developing pancreatic tumours.Other therapeutic agents for which polymorphic N-acetylation plays a minor role in their metabolism have been investigated but any impact of this metabolic difference on clinical efficacy or associated toxicity is still under question. In the search for clues as to the underlying aetiology, patient groups with many disease states have been examined for association with differences in N-acetylation and the majority have provided data that could be interpreted as equivocal. Studies have given contradictory, often opposing, results, calculated risk factors that are (perhaps) just significant but certainly not high, and patients within the cohorts who are always exceptions. Undoubtedly, other as yet unappreciated factors are at play.

Pharmacogenetics and drug metabolism: historical perspective and appraisal.

The events leading up to the discovery of genetically controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field.The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a success or failure within the present clinical arena.

Phenylalanine 4-monooxygenase: the "sulfoxidation polymorphism".

1. Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-l-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age.2. Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-l-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders; although, underlying mechanisms were unknown.3. Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.

The S-oxidation of S-carboxymethyl-L-cysteine in hepatic cytosolic fractions from BTBR and phenylketonuria enu1 and enu2 mice.

Mice that were heterozygous dominant for the enu1 and enu2 mutation in phenylalanine monooxygenase/phenylalanine hydroxylase (PAH) resulted in hepatic PAH assays for S-carboxymethyl-L-cysteine (SCMC) that had significantly increased calculated Km (wild type (wt)/enu1, 1.84-2.12 fold increase and wt/enu2 a 2.75 fold increase in PAH assays). The heterozygous dominant phenotypes showed a significantly reduced catalytic turnover of SCMC (wt/enu1, 6.11 fold decrease and wt/enu2 an 11.25 fold decrease in calculated Vmax). Finally, these phenotypes also had a significantly reduced clearance, CLE (wt/enu1, 13.02 fold and wt/enu2, a 30.80-30.94 fold decrease) The homozygous recessive phenotype (enu1/enu1) was also found to have significantly increased calculated Km (2.16 fold increase), a significantly reduced calculated Vmax (11.35-12.33 fold decrease) and CLE (24.75-25.00 fold decrease). The enu2/enu2, homozygous recessive phenotype had no detectable PAH activity using SCMC as substrate. The identity of the enzyme responsible for the C-oxidation of L-phenylalanine (L-Phe) and the S-oxidation of SCMC in wt/wt (BTBR) mice was identified using monoclonal antibody and selective chemical inhibitors and was found to be PAH. This in vitro mouse hepatic cytosolic fraction metabolism investigation provides further evidence to support the hypothesis that an individual possessing one variant allele for PAH will result in a poor metaboliser phenotype that is unable to produce significant amounts of S-oxide metabolites of SCMC.

Xenobiotic C-sulfonate derivatives; metabolites or metabonates?

1. The production of sulfate conjugates is a well-known and established pathway within the field of xenobiotic metabolism. In addition to the usual attachment of a sulfonate grouping via an oxygen atom (O-sulfonates) to yield a sulfate conjugate, so-called "N-sulfates" (N-sulfonates) have been reported and "S-sulfates" (S-sulfonates) mooted to exist. 2. The few examples cited in the literature where the sulfur atom of the sulfonate group was attached directly to a carbon atom of the xenobiotic (C-sulfonates) and subsequently excreted as a metabolite have been collated, examined and reviewed. 3. The potential mechanisms of formation of these C-sulfonates are discussed, both biological and chemical; the potential role of the gut microbiome raised and hopefully by highlighting this curiosity further fruitful investigation will be stimulated.

Trimethylamine-The Extracorporeal Envoy.

One of the most widespread and efficient mechanisms that has evolved to enable communication between discrete and spatially separate living organisms is the use of specific chemical messengers. The organoleptic properties of certain molecules, even at concentrations that do not necessarily evoke a conscious response, have been exploited to transmit information across relatively large distances. The trimethylated derivative of ammonia is one such molecule that is ideally suited to this function and several species are known to respond to its presence. This review uniquely collects together and integrates widely dispersed data to show that trimethylamine also may serve a communicatory role in man, with its influence extending outside of the body.

Xenobiotic conjugation with phosphate - a metabolic rarity.

1. Although not unknown, the conjugation of a xenobiotic with phosphate appears a rarity amongst the routes available for foreign compound metabolism. This is especially true in mammals and may be somewhat surprising as conjugation with sulphate, a seemingly similar moiety, is commonplace. 2. Information from the literature, where xenobiotic phosphate conjugates have been described or suggested, has been collated and presented in this article. By bringing together this diverse material, hopefully interest will be generated in this unusual xenobiotic reaction, and perhaps further research undertaken to better understand and delineate the reasons for its relative absence from the xenobiotic scene.

Sulphate absorption across biological membranes.

1. Sulphonation is unusual amongst the common Phase II (condensation; synthetic) reactions experienced by xenobiotics, in that the availability of the conjugating agent, sulphate, may become a rate-limiting factor. This sulphate is derived within the body via the oxygenation of sulphur moieties liberated from numerous ingested compounds including the sulphur-containing amino acids. Preformed inorganic sulphate also makes a considerable contribution to this pool. 2. There has been a divergence of opinion as to whether or not inorganic sulphate may be readily absorbed from the gastrointestinal tract and this controversy still continues in some quarters. Even more so, is the vexing question of potential absorption of inorganic sulphate via the lungs and through the skin. 3. This review examines the relevant diverse literature and concludes that sulphate ions may move across biological membranes by means of specific transporters and, although the gastrointestinal tract is by far the major portal of entry, some absorption across the lungs and the skin may take place under appropriate circumstances.

Phenylalanine monooxygenase and the sulfur oxygenation of S-carboxymethyl-L-cysteine in mice.

1. The extent of sulfoxidation of the drug, S-carboxymethyl-L-cysteine, has been shown to vary between individuals, with this phenomenon being mooted as a biomarker for certain disease states and susceptibilities. Studies in vitro have indicated that the enzyme responsible for this reaction was phenylalanine monooxygenase but to date no in vivo evidence exists to support this assumption. Using the mouse models of mild hyperphenylalaninamia (enu1 PAH variant) and classical phenylketonuria (enu2 PAH variant), the sulfur oxygenation of S-carboxymethyl-L-cysteine has been investigated. 2. Compared to the wild type (wt/wt) mice, both the heterozygous dominant (wt/enu1 and wt/enu2) mice and the homozygous recessive (enu1/enu1 and enu2/enu2) mice were shown to have significantly increased Cmax, AUC(0-180 min) and AUC(0-∞ min) values (15 - to 20-fold higher). These results were primarily attributable to the significantly reduced clearance of S-carboxymethyl-L-cysteine (13 - to 22-fold lower). 3. Only the wild type mice produced measurable quantities of the parent S-oxide metabolites. Those mice possessing one or more allelic variant showed no evidence of blood SCMC (R/S) S-oxides. These observations support the proposition that differences in phenylalanine hydroxylase activity underlie the variation in S-carboxymethyl-L-cysteine sulfoxidation and that no other enzyme is able to undertake this reaction.

S-carboxymethyl-L-cysteine and it (R/S)-S-oxides in beagle dog plasma and hepatic cytosol.

1. Incubation of beagle hepatic cytosol, under conditions promoting phenylalanine hydroxylase activity, led to the formation of the sulfoxide derivatives of S-carboxymethyl-L-cysteine, N-acetyl-S-carboxymethyl-L-cysteine, S-methyl-L-cysteine and N-acetyl-S-methyl-L-cysteine. Thiodiglycolic acid was not a substrate. Enzyme kinetic parameters (Km, Vmax) were derived indicating S-carboxymethyl-L-cysteine had the greatest clearance; no enantioselective preference was observed for this S-oxygenation reaction. 2. Following oral administration of S-carboxymethyl-L-cysteine to beagle dogs, the parent substance and its sulfoxide were the only compounds identified in the plasma. Pharmacokinetic data have been obtained indicating that the small amount of sulfoxide formed persisted within the body for longer than the parent material, but that the majority of the ingested dose remained in the administered sulfide form. 3. The sulfide moiety within the muco-regulatory drug, S-carboxymethyl-L-cysteine, is thought to be vital as it acts as a free radical scavenger, resulting in the inactive sulfoxide. Additional extensive enyzme-mediated sulfoxidation would decrease the amount of active sulfide available. In the dog this appears to not be an issue, signalling possible exploitation for therapeutic benefit in treating airway disease.

Xenobiotic-urea conjugates; chemical or biological?

1. Although the major pathways involved in drug metabolism have been elucidated, there remain those routes that may be considered as minor, esoteric, or even artifactual. 2. Conjugation with urea, an abundant, non-toxic, small water soluble molecule, is such a disputed and debatable Phase II pathway. 3. The present article collates data gleaned from the literature concerning xenobiotic-urea conjugation, presents pertinent information resurrecting the controversy and poses questions as to the nature of the phenomenon.

Ethyl sulphate, a chemically reactive human metabolite of ethanol?

1. Ethanol consumption is known to be linked in varying degrees to numerous ailments including damage to the nervous, endocrine and musculoskeletal systems and the gastrointestinal tract as well as extensive liver injury and several cancerous events. 2. Although acetaldehyde is the presently favoured candidate, both directly and indirectly, for such deleterious outcomes, over the years many other mechanisms and suggestions have been advanced. 3. The sparse literature concerning ethyl sulphate, a recently confirmed human metabolite of ethanol, has been examined, evaluated and interpreted to put forward the new proposition that ethyl sulphate itself may be able to alkylate various biological macromolecules thereby leading to toxicity.

Curiosities in drug metabolism.

1. It is inevitable that during some xenobiotic biotransformation studies, a certain metabolite or degradation product arises of which the identity is uncertain, the route of formation is ambiguous, or it is just a plain mystery. 2. The following communication draws attention to three drugs reported in the literature, chlorphentermine, phenothiazine and aminopyrine, where after many years of investigation there still exists uncertainty over some of their metabolites. Noticeably, these three examples probably involve (potential) interaction of a nitrogen centre within the drug molecule. 3. It is hoped that the resurrection and assemblage of these data will offer interesting reading and that these examples may prove sufficiently intriguing to motivate further exploration and some resolution of these lingering concerns.

Asparagus, urinary odor, and 1,2-dithiolane-4-carboxylic acid.

The derivatives of 1,2-dithiolane are scattered widely throughout the natural world where they are generally exploited for their biocidal properties. One of these, known as asparagusic acid (1,2-dithiolane-4-carboxylic acid), is present in the frequently consumed vegetable, asparagus, and though apparently innocuous toxicologically, it may be responsible for the distinctive urine odor produced after consuming this food. This review collects together, for the first time, historical observations associating asparagus ingestion with this unique odor-producing phenomenon and collates data implicating a 1,2-dithiolane structure as the major chemical precursor responsible.

A randomized study of sodium hypochlorite versus formocresol pulpotomy in primary molar teeth.

BACKGROUND: Alternatives to vital pulpotomy treatment in primary teeth are being sought because of the high formaldehyde content of traditional formocresol (FC) pulpotomy medicaments. AIM: The aim was to compare the clinical and radiographic success of vital pulpotomy treatment in primary molars using 3% sodium hypochlorite (NaOCl) versus a 1:5 dilution of Buckley's FC. DESIGN: Pulpotomies were performed in primary molars of healthy children between 3 and 10 years old. Sixty-five primary teeth were randomized into two groups that were evaluated for treatment outcomes. Following treatment, the pulp chamber was filled with zinc oxide eugenol (ZnOE) and restored with a stainless steel crown cemented with glass ionomer cement. Clinical and radiographic outcomes were recorded at 6 and 12 months. RESULTS: The control (FC) and experimental (NaOCl) groups demonstrated 100% clinical success at 6 and 12 months. The NaOCl group had 86% (19/22) radiographic success at 6 months and 80% (12/15) at 12 months. The FC group had 84% (21/25) radiographic success at 6 months and 90% (9/10) at 12 months. No significant differences were found in the radiographic outcomes between the two groups at 6 and 12 months (Fisher's exact test; P=0.574 and P=0.468, respectively). CONCLUSION: NaOCl demonstrated clinical and radiographic success comparable to FC.

An investigation into possible xenobiotic-endobiotic inter-relationships involving the amino acid analogue drug, S-carboxymethyl-L-cysteine and plasma amino acids in humans.

The amino acid derivative, S-carboxymethyl-L-cysteine, is an anti-oxidant agent extensively employed as adjunctive therapy in the treatment of human pulmonary conditions. A major biotransformation route of this drug, which displays considerable variation in capacity in man, involves the oxidation of the sulfide moiety to the inactive S-oxide metabolite. Previous observations have indicated that fasted plasma L-cysteine concentrations and fasted plasma L-cysteine/free inorganic sulfate ratios were correlated with the degree of sulfoxidation of this drug and that these particular parameters may be used as endobiotic biomarkers for this xenobiotic metabolism. It has been proposed also that the enzyme, cysteine dioxygenase, was responsible for the drug sulfoxidation. Further in this theme, the degree of S-oxidation of S-carboxymethyl-L-cysteine in 100 human volunteers was investigated with respect to it potential correlation with fasted plasma amino acid concentrations. Extensive statistical analyses showed no significant associations or relationships between the degree of drug S-oxidation and fasted plasma amino acid concentrations, especially with respect to the sulfur-containing compounds, methionine, L-cysteine, L-cysteine sulfinic acid, taurine and free inorganic sulfate, also the derived ratios of L-cysteine/L-cysteine sulfinic acid and L-cysteine/free inorganic sulfate. It was concluded that plasma amino acid levels or derived ratios cannot be employed to predict the degree of S-oxidation of S-carboxymethyl-L-cysteine (or vice versa) and that it is doubtful if the enzyme, cysteine dioxygenase, has any involvement in the metabolism of this drug.

Efficacy of Early Preventive Dental Services in Primary Medical Care Setting: Results From Alabama's 1st Look Program.

Purpose: To evaluate early preventive dental services (PDS) provided by primary care providers (PCPs) in reducing future caries treatments among Alabama Medicaid recipients. Methods: Data from 2009 to 2019 Alabama Medicaid were used to evaluate effectiveness of 1st Look Program on PDS before age three years and incidence of caries treatments after age three years. PDS groups consisted of 1st Look-involved (PDS claims from PCPs), dentist-only (PDS claims from dental providers), and no early fluoride treatment participants (no PDS claims before age three years). Outcomes included frequency and expenditures of fluoride applications, simple restorations, and extensive treatments. Regression models were used to evaluate associations between PDS groups and outcomes while controlling for covariates. Results: Children in 1st Look- involved received more fluoride (3.0 versus 2.1 times; P<0.001) and were applied earlier (12.1 versus 22.9 months old; P<0.001) than dentist-only group. After adjusting for covariates, compared to dentist-only, 1st Look-involved group received earlier fluoride (beta value equals -11.1 months; 95 percent confidence interval [95% CI] equals -11.25 to -10.97) with greater frequency (incident rate ratio equals 1.49; 95% CI equals 1.47 to 1.51). Caries treatment counts were highest in dentist-only followed by 1st Look-involved and no early fluoride treatment groups in both simple restorations (2.7 versus 2.0 versus 0.2 times; P<0.001) and extensive treatments (2.8 versus 2.3 versus 0.2 times; P<0.001), which were consistent after adjusting for covariates. Conclusions: PDS were provided earlier by PCPs in Medicaid-qualified children, with reduced caries treatments on primary teeth, compared to PDS by dental providers only.

Nutrition and sulfur.

Sulfur is unusual in that it is a mineral that may be taken into the body in both inorganic and organic combinations. It has been available within the environment throughout the development of lifeforms and as such has become integrated into virtually every aspect of biochemical function. It is essential for the nature and maintenance of structure, assists in communication within the organism, is vital as a catalytic assistant in intermediary metabolism and the mechanism of energy flow as well as being involved in internal defense against potentially damaging reactive species and invading foreign chemicals. Recent studies have suggested extended roles for sulfur-containing molecules within living systems. As such, questions have been raised as to whether or not humans are receiving sufficient sulfur within their diet. Sulfur appears to have been the "poor relation" with regards to mineral nutrition. This may be because of difficulties encountered over its multifarious functions, the many chemical guises in which it may be ingested and its complex biochemical interconversions once taken into the body. No established daily requirements have been determined, unlike many minerals, although suggestions have been proposed. Owing to its widespread distribution within dietary components its intake has almost been taken for granted. In the majority of individuals partaking of a balanced diet the supply is deemed adequate, but those opting for specialized or restrictive diets may experience occasional and low-level shortages. In these instances, the careful use of sulfur supplements may be of benefit.

Community dental health coordinators' role in community-based pediatric dental education.

PURPOSE: The University of Alabama at Birmingham (UAB) School of Dentistry utilized a Community Dental Health Coordinator (CDHC) to transform a community-based dental education rotation into a positive learning experience for senior dental students. Based in a county health department's Women, Infant, and Children's (WIC) clinic and dental clinic, the initial rotation before implementation of the CDHC was received poorly by students and community partners. This paper reports how CDHC involvement improved student experiences with pediatric patients. METHODS: In 2018, the CDHC embedded in the WIC clinic where student rotations occur and developed relationships with the community partners to identify key issues. The CDHC then implemented qualitative improvements, including a restructured workflow, preparatory educational modules, and assessment systems to address the issues. Student performance reports, focus group discussions, and a postgraduation questionnaire provided data for evaluation of performance. RESULTS: By year 3, dental appointments for patients under age 6 increased, resulting in 95% of UAB students seeing this age patient; 74% completed four or more. Three-quarters of students reported performing restorative procedures on children. Student and community partner acceptance of the rotation also improved. Postgraduation questionnaires (32% response rate) indicate 35% of graduates continue to treat Medicaid patients after graduation. CONCLUSION: The CDHC's unique skills in community relationship-building, community-based dental screenings, and pediatric dental care coordination produced measurable improvements in community participation and student clinical experiences. The CDHC can be a vital part of dental education, especially in community education settings. Community-based dental education generated measurable improvements in students' clinical experiences.