Current status and usefulness of therapeutic drug monitoring implementation of theophylline in elderly patients based on a nationwide database study and modeling approach.

OBJECTIVES: Theophylline is used in the treatment of chronic obstructive pulmonary disease but readily causes symptoms of intoxication and exhibits high risks in elderly patients. However, there have only been a few recent reports on the significance of therapeutic drug monitoring (TDM) implementation, especially in elderly patients. To examine the usefulness of theophylline TDM, we evaluated the current status of prescriptions containing theophylline and its side effects and assessed the influence of aging, sex, drug formulation, and concurrent drugs use on theophylline exposure using data from various nationwide databases and a pharmacokinetic modeling approach. METHODS: We utilized sampling data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Using the data of patients aged ≥80 years, we conducted an association analysis of theophylline and concurrent drugs. The transition in plasma theophylline concentration levels of elderly patients was estimated based on a previously reported physiological-based pharmacokinetic model. RESULTS: Altogether, 3973 patients using theophylline were registered in our dataset, and about 50% were over 70 years old and used theophylline. Therapeutic drug monitoring implementation was confirmed in only 1.13% of patients. The association analysis confirmed a frequent co-occurrence with allopurinol and famotidine, which increase theophylline exposure, in elderly patients aged ≥80 years. The physiologically based pharmacokinetic model indicated that theophylline trough concentrations were 1.65-fold higher in elderly patients aged 80 years compared to those aged 30 years and 1.35-fold higher in females compared to males. CONCLUSION: This study effectively combined information on the nationwide health care database and modeling approach, indicating the importance of proactive TDM and dose justification for female and elderly patients.

Characterization of a Soft Ionization by Chemical Reaction in Transfer Ion Source Hyphenated With Supercritical Fluid Chromatography-Tandem Mass Spectrometry.

A commercially available dielectric barrier discharge ionization (DBDI) source was tested with supercritical fluid chromatography-mass spectrometry (SFC-MS). The compound mixture investigated comprised caffeine, theobromine, theophylline, uracil, testosterone, and pyrene, diluted in methanol. Dynamic response ranges were evaluated with multiple injections at different concentrations. Precision studies demonstrated the robustness and sensitivity of the ionization source across a concentration range of 10-1000 ng/mL. Results from this experiment showed linear regression of 0.99 or greater for all analytes tested over the range with a relative standard deviation (RSD) of less than 10% down to 10 ng/mL for all analytes except theobromine, which had an RSD of less than 10% down to 25 ng/mL. Notably, this study marks the first investigation of sensitivity for coupling a commercial DBDI source with SFC; a limit of detection less than 1 ng/mL was achieved for all compounds. This study demonstrates chromatographic separation by SFC and MS analysis for compounds that ionize poorly using traditional atmospheric pressure ionization, such as polycyclic aromatic hydrocarbons. Combining SFC with the DBDI source opens promising avenues for analyzing compounds that were previously challenging to characterize with standard atmospheric pressure ionization techniques.

Cough-induced severe bradycardia and syncope in a dog.

A 10-year-old spayed female shih tzu dog was brought to the hospital because of recurring syncope that occurred simultaneously with a cough. Physical examination did not reveal an abnormal heart rhythm or abnormal heart sounds. Electrocardiography revealed sinus arrest of 4.7 s with intermittent escape beats during coughing. Additional examinations, including thoracic radiography, clinical pathology, and echocardiography, revealed no abnormalities of concern. Forty-eight-hour Holter monitoring captured 1 syncopal episode following severe coughing, during which the longest sinus arrest lasted 16 s with intermittent escape beats. This observation confirmed our strong suspicion that coughing was the cause of varying degrees of sinus arrest in this dog. Theophylline, codeine, and short-term prednisolone were prescribed to treat the dog's cough. The daily episodes of syncope ceased and coughing decreased. Subsequent 48-hour Holter monitoring revealed no abnormal pauses, and the owner did not report syncope. Theophylline and codeine were continued for 5 mo, during which time no syncope occurred. To our knowledge, this case provides the first clear evidence of a correlation between cough-induced sinus arrest and syncope in a veterinary patient, as confirmed by Holter monitoring and electrocardiography. Key clinical message: Cough-induced severe bradycardia and syncope were identified in a shih tzu dog. After the antitussive medication was adjusted, the signs resolved.

Bradycardie sévère et syncope provoquées par la toux chez un chienUne chienne shih tzu stérilisée âgée de 10 ans a été amenée à l'hôpital en raison d'une syncope récurrente survenue simultanément avec une toux. L'examen physique n'a révélé aucun rythme cardiaque anormal ni bruits cardiaques anormaux. L'électrocardiographie a révélé un arrêt sinusal de 4,7 s avec des battements d'échappements intermittents lors de la toux. Des examens complémentaires, notamment une radiographie thoracique, des analyses en pathologie clinique et une échocardiographie, n'ont révélé aucune anomalie préoccupante. Une surveillance Holter de 48 heures a capturé 1 épisode syncopal à la suite d'une toux sévère, au cours duquel l'arrêt sinusal le plus long a duré 16 s avec des battements d'échappements intermittents. Cette observation a confirmé nos fortes suspicions selon lesquelles la toux était la cause de divers degrés d'arrêt sinusal chez ce chien. De la théophylline, de la codéine et de la prednisolone de courte durée ont été prescrites pour traiter la toux du chien. Les épisodes quotidiens de syncope ont cessé et la toux a diminué. Une surveillance Holter ultérieure de 48 heures n'a révélé aucune pause anormale et le propriétaire n'a pas signalé de syncope. La théophylline et la codéine ont été poursuivies pendant 5 mois, période pendant laquelle aucune syncope ne s'est produite. À notre connaissance, ce cas constitue la première preuve claire d'une corrélation entre l'arrêt sinusal induit par la toux et la syncope chez un patient vétérinaire, comme le confirme la surveillance Holter et l'électrocardiographie.Message clinique clé :Une bradycardie et une syncope sévères induites par la toux ont été identifiées chez un chien shih tzu. Après ajustement du traitement antitussif, les signes ont disparu.(Traduit par Dr Serge Messier).

How Does the Powder Mixture of Ibuprofen and Caffeine Attenuate the Solubility of Ibuprofen? Comparative Study for the Xanthine Derivatives to Recognize Their Intermolecular Interactions Using Fourier-Transform Infrared (FTIR) Spectra, Differential Scanning Calorimetry (DSC), and X-ray Powder Diffractometry (XRPD).

Molecular interactions between active pharmaceutical ingredients (APIs) and xanthine (XAT) derivatives were analyzed using singular value decomposition (SVD). XAT derivatives were mixed with equimolar amounts of ibuprofen (IBP) and diclofenac (DCF), and their dissolution behaviors were measured using high-performance liquid chromatography. The solubility of IBP decreased in mixtures with caffeine (CFN) and theophylline (TPH), whereas that of DCF increased in mixtures with CFN and TPH. No significant differences were observed between the mixtures of theobromine (TBR) or XAT with IBP and DCF. Mixtures with various molar ratios were analyzed using differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared spectroscopy to further explore these interactions. The results were subjected to SVD. This analysis provides valuable insights into the differences in interaction strength and predicted interaction sites between XAT derivatives and APIs based on the combinations that form mixtures. The results also showed the impact of the XAT derivatives on the dissolution behavior of IBP and DCF. Although IBP and DCF were found to form intermolecular interactions with CFN and TPH, these effects resulted in a reduction of the solubility of IBP and an increase in the solubility of DCF. The current approach has the potential to predict various interactions that may occur in different combinations, thereby contributing to a better understanding of the impact of health supplements on pharmaceuticals.

Harnessing chemical functionality of xylan hemicellulose towards carbohydrate polymer-based pH/magnetic dual-responsive nanocomposite hydrogel for drug delivery.

This study reports a pH/magnetic dual-responsive hemicellulose-based nanocomposite hydrogel with nearly 100 % carbohydrate polymer-based and biodegradable polymer compositions for drug delivery. We synthesized pure Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) using a co-precipitation method, then engineering xylan hemicellulose (XH), acrylic acid, poly(ethylene glycol) diacrylate, and Fe3O4 to synthesize the pH/magnetic dual-responsive hydrogel (Fe3O4@XH-Gel), through graft polymerization on XH with in-situ doping Fe3O4 MNPs initiated by the ammonium persulfate/tetramethylethylenediamine redox system. Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (1H NMR), X-ray diffractometry (XRD), scanning electron microscopy and energy dispersive spectrometer (SEM-EDS), high-resolution transmission electron microscopy (HRTEM), Brunauer-Emmett-Teller (BET), swelling gravimetric analysis, vibrating sample magnetometer (VSM) were employed to analyze the hydrogel's chemical structures, morphologies, pH-responsive behaviors, and magnetic responsiveness characteristics, mechanical and rheological properties, as well as cytotoxicity and biodegradability. The results indicate that the Fe3O4@XH-Gel exhibited excellent dual responsiveness to pH and magnetism. Furthermore, an emphasis was placed on the in-depth analysis of the pH response mechanism. Finally, we utilized this cutting-edge hydrogel to investigate the controlled-release behavior of two model drugs, Acetylsalicylic acid and Theophylline. The hydrogel demonstrated exceptional controlled release attributes, positioning it as a potential carrier for targeted drug delivery, particularly to the gastrointestinal conditions.

Truncations and in silico docking to enhance the analytical response of aptamer-based biosensors.

Aptamers are short oligonucleotides capable of binding specifically to various targets (i.e., small molecules, proteins, and whole cells) which have been introduced in biosensors such as in the electrochemical aptamer-based (E-AB) sensing platform. E-AB sensors are comprised of a redox-reporter-modified aptamer attached to an electrode that undergoes, upon target addition, a binding-induced change in electron transfer rates. To date, E-AB sensors have faced a limitation in the translatability of aptamers into the sensing platform presumably because sequences obtained from Systematic Evolution of Ligands by Exponential Enrichment (SELEX) are typically long (>80 nucleotides) and that obtaining structural information remains time and resource consuming. In response, we explore the utility of aptamer base truncations and in silico docking to improve their translatability into E-AB sensors. Here, we first apply this to the glucose aptamer, which we characterize in solution using NMR methods to guide design and translate truncated variants in E-AB biosensors. We further investigated the applicability of the truncation and computational approaches to four other aptamer systems (vancomycin, cocaine, methotrexate and theophylline) from which we derived functional E-AB sensors. We foresee that our strategy will increase the success rate of translating aptamers into sensing platforms to afford low-cost measurements of molecules directly in undiluted complex matrices.

N6-cyclohexyladenosine is better than meperidine and buspirone at suppressing metabolism during TTM32 but does not improve outcome after cardiac arrest.

N6-clyclohexyladenosine (CHA) is an adenosine A1 receptor agonist that inhibits thermogenesis. Cardiovascular side effects however, limit use of CHA as a therapeutic. We and others have shown that this can be reversed by administering 8-p-(sulfophenyl)theophylline (8-SPT), a nonspecific antagonist that does not cross the BBB. Other evidence shows that CNS actions of CHA may contribute to bradycardia through enhanced vagal tone and other mechanisms. Here we test the hypothesis that 8-SPT pretreatment alone is sufficient to prevent hypotension caused by CHA. To test this hypothesis, we pretreated rats with 8-SPT alone, and in combination with other antagonists to test the hypothesis that direct action of CHA on the heart is the primary mechanism by which CHA induces bradycardia and hypotension. Results show that pretreatment with 8-SPT alone is not sufficient to prevent CHA-induced hypotension. Pretreatment with 8-SPT or atropine alone did not prevent the fall in mean arterial pressure (MAP) and heart rate (HR), however, pretreatment with 8-SPT (25 mg/kg) and atropine (1 mg/kg) 15 min before CHA (1 mg/kg) preserves MAP and HR baseline values after CHA administration. We next asked if blood pressure was managed during the transition into a hypometabolic state, would prolong CHA-mediated inhibition of metabolism after cardiac arrest improve outcome better than anti-shivering medications meperidine and buspirone. We found that CHA-mediated hypotension can be mitigated by pretreatment with atropine and 8-SPT. This combination administered after cardiac arrest facilitated temperature management and metabolic suppression better than meperidine and buspirone, however, did not improve survival.

Safety Assessment of Methylxanthines as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of three methylxanthines, Caffeine, Theobromine, and Theophylline, as used in cosmetics. All of these ingredients are reported to function as skin-conditioning agents in cosmetic products. The Panel reviewed the data relevant to the safety of these ingredients and concluded that Caffeine, Theobromine, and Theophylline are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Sex Dependence in Control of Renal Haemodynamics and Excretion in Streptozotocin Diabetic Rats-Role of Adenosine System and Nitric Oxide.

Recently, we compared an interplay of the adenosine system and nitric oxide (NO) in the regulation of renal function between male normoglycaemic (NG) and streptozotocin-induced diabetic rats (DM). Considering the between-sex functional differences, e.g., in the NO status, we present similar studies performed in female rats. We examined if the theophylline effects (non-selective adenosine antagonist) in NG and DM females with or without active NO synthases differed from the earlier findings. In anaesthetised female Sprague Dawley rats, both NG and DM, untreated or after NO synthesis blockade with L-NAME, theophylline effects, on blood pressure, renal hemodynamics and excretion, and renal tissue NO were investigated. Renal artery blood flow (Transonic probe), cortical, outer-, and inner-medullary flows (laser-Doppler technique), and renal tissue NO signal (selective electrode) were measured. In contrast to males, in female NG and DM rats, theophylline induced renal vasodilation. In NO-deficient females, theophylline induced comparable renal vasodilatation, confirming the vasoconstrictor influence of the renal adenosine. In NG and DM females with intact NO synthesis, adenosine inhibition diminished kidney tissue NO, contrasting with an increase reported in males. Lowered baseline renal excretion in DM females suggested stimulation of renal tubular reabsorption due to the prevalence of antinatriuretic over natriuretic tubular action of adenosine receptors. An opposite inter-receptor balance pattern emerged previously from male studies. The study exposed between-sex functional differences in the interrelation of adenosine and NO in rats with normoglycaemia and streptozotocin diabetes. The findings also suggest that in diabetes mellitus, the abundance of individual receptor types can distinctly differ between females and males.

Role of Doxofylline, Low Dose Theophylline, and Dexamethasone in Mice (BALB/C) Model of Corticosteroid Resistant Asthma: A Comparative Study.

OBJECTIVE: This study was designed to determine the comparative efficacy of Doxofylline (DOXO) compared to low-dose theophylline (LDT) in treating corticosteroid-resistant asthma. METHODS: This study was conducted on 56 adult BALB/C mice aged six to eight weeks old with an average weight of 20-25 g. They were divided into seven groups: control group, ovalbumin (OVA)+lipopolysaccharide (LPS) group, OVA+LPS+dexamethasone (DEXA) group, OVA+LPS+LDT group, OVA+LPS+ group, OVA+LPS+DEXA+LDT group, and OVA +LPS+DEXA+DOXO group. All mice were administered IP DOXO+DEXA. All the doses were administrated one day before the first challenge and lasted for five consecutive days after one hour of the OVA challenge until sacrificed. Lung biochemical parameters, including interleukin (IL)-2, IL-4, IL-8, IL-10, and IL-17 levels, were measured using enzyme-linked immunosorbent assay (ELISA). In addition, Histone deacetylase (HDAC) activity and lung histological analysis were also performed. Furthermore, the glucocorticoid receptor was measured by nexttec™. RESULTS: The OVA+LPS group exhibited significantly (p<0.05) elevated levels of interleukin (IL)-2, IL-4, IL-8, IL-10, and IL-17 compared to controls, indicative of airway inflammation. Moreover, OVA+LPS induction significantly (p<0.05) increased the levels of Interferon-gamma (IFN-γ), NF[Formula: see text]B, Tumor Necrosis Factor (TNFα), and Immunoglobulin E (IgE) parameters, indicating severe inflammation and immune response and successfully induced the disease model. Meanwhile, LDT and DOXO in conjunction with DEXA, further augmented HDAC2 activity compared to DEXA alone. Similarly, the administration of LDT increased the expression of GR by 64.5% (23.72±0.34), while DOXO increased the expression of GR by 94.10% (27.99±0.15), which restores it back to control. Furthermore, according to Hematoxylin and eosin (H&E) stained sections, the DOXO group exhibited a slight improvement in these histopathological features, suggesting a modest therapeutic effect. Masson's Trichrome staining showed a slightly improved patchy collagen deposition within alveolar spaces in intra-alveolar and interstitial inflammatory cell accumulation in DOXO group, and the combination of these drugs (DEXA+LDT group) improved collagen deposition moderately within alveolar spaces in intra-alveolar and interstitial inflammatory cell accumulation. Overall, treatment with DOXO, LDT alone, and with DEXA combination led to reductions in cytokine levels, with DOXO and LDT showing significant (p<0.05) efficacy to DEXA used alone, which showed non-significant (p>0.05) efficacy. CONCLUSIONS: Doxofylline and LDT were found to be effective therapeutic agents when used alone or in combination with Dexamethasone. However, randomized controlled trials are required to evaluate its further efficacy.

Tuning bio-aerogel properties. Part 3: Exploring silica-pectin composite aerogels for drug delivery.

The release of the model drug theophylline from silica-pectin aerogels was investigated. The composite aerogels were prepared via impregnation of pectin alcogels with silica sol, followed by in situ silica gelation and drying with supercritical CO2. The structural and physico-chemical properties of the aerogels were tuned via the preparation conditions (type of silica sol, calcium crosslinking of pectin or not). Theophylline was loaded via impregnation and its release into simulated gastric fluid was studied during 1 h followed by release into simulated intestinal fluid. The swelling, mass loss and theophylline release behavior of the composites were analyzed and correlated with material properties. It followed that only aerogels prepared with calcium-crosslinked pectin and polyethoxydisiloxane were stable in aqueous systems, exhibiting a slow theophylline release governed by near-Fickian diffusion.

Computational and in vitro binding studies of theophylline against phosphodiesterases functioning in sperm in presence and absence of pentoxifylline.

Fertility is a result of a synergy among the sperm's various functions including capacitation, motility, chemotaxis, acrosome reaction, and, finally, the fertilization of the oocyte. Subpar motility is the most common cause of infertility in males. Cyclic adenosine monophosphate (cAMP) signalling underlies motility and is depleted by the phosphodiesterases (PDEs) in sperm, such as PDE10A, PDE1, and PDE4. Therefore, the PDE inhibitor (PDEI) category of fertility drugs aim to enhance motility in assisted reproduction technologies (ARTs) through inhibition of PDEs, though they might have adverse effects on other physiological variables. For example, the popular drug pentoxifylline (PTX), widely used in ARTs, improves motility but causes premature acrosome reaction and exerts toxicity on the fertilized oocyte. Another xanthine-derived drug, theophylline (TP), has been repurposed for treating infertility, but its mechanism of PDE inhibition remains unexplored. Here, using biophysical and computational approaches, we identified that TP binds to the same binding pocket as PTX with higher affinity than PTX. We also found that PTX and TP co-bind to the same binding pocket, but at different sites.

Evaluation and clinical application of a bracketing calibration-based isotope dilution liquid chromatography-tandem mass spectrometry candidate reference measurement procedure for serum theophylline.

A candidate reference measurement procedure (RMP) for serum theophylline via isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. With a single-step precipitation pretreatment and a 6-min gradient elution, the method achieved baseline separation of theophylline and its analogs on a C18-packed column. A bracketing calibration method was used to ensure repeatable signal intensity and high measurement precision. The intra-assay and inter-assay imprecisions were 1.06%, 0.84%, 0.72% and 0.47%, 0.41%, 0.25% at concentrations of 4.22 µg/mL (23.40 µmol/L), 8.45 µg/mL (46.90 µmol/L), and 15.21 µg/mL (84.43 µmol/L), respectively. Recoveries ranged from 99.35 to 102.34%. The limit of detection (LoD) was 2 ng/mL, and the lowest limit of quantification (LLoQ) was 5 ng/mL. The linearity range extended from 0.47 to 60 µg/mL (2.61-333.04 µmol/L). No ion suppression and carry-over (< 0.68%) were observed. The relative bias for this candidate RMP that participated in 2023 External Quality Control for Reference Laboratories (RELA) conducted by the International Federation of Clinical Chemistry (IFCC) was within a range of 0.17 to 0.93%. Furthermore, two clinical immunoassay systems were compared with this candidate RMP, demonstrating good correlations. The results of the Trueness Verification Plan indicate significant differences among routine systems, highlighting the need for standardization efforts. The developed candidate RMP for serum theophylline serves as a precise reference baseline for standardizing clinical systems and assigning values to reference materials.

Circadian time-dependent effects of experimental colitis on theophylline disposition and toxicity.

BACKGROUND AND PURPOSE: Drug disposition undergoes significant alteration in patients with inflammatory bowel disease (IBD), yet circadian time-dependency of these changes remains largely unexplored. In this study, we aimed to determine the temporal effects of experimental colitis on drug disposition and toxicity. EXPERIMENTAL APPROACH: RNA-sequencing was used to screen genes relevant to colitis induced by dextran sodium sulfate in mice. Liver microsomes and pharmacokinetic analysis were used to analyze the activity of key enzymes. Dual luciferase assays and chromatin immunoprecipitation (ChIP) were employed to elucidate regulatory mechanisms. KEY RESULTS: RNA sequencing analysis revealed that colitis markedly influenced expression of cytochrome P450 (CYP) enzymes. Specifically, a substantial down-regulation of CYP1A2 and CYP2E1 was observed in livers of mice with colitis at Zeitgeber Time 8 (ZT8), with no significant changes detected at ZT20. At ZT8, the altered expression corresponded to diminished metabolism and enhanced incidence of hepato-cardiac toxicity of theophylline, a substrate specifically metabolized by these enzymes. A combination of assays, integrating liver-specific Bmal1 knockout and targeted activation of BMAL1 showed that dysregulation in CYP1A2 and CYP2E1 during colitis was attributable to perturbed BMAL1 functionality. Luciferase reporter and ChIP assays collectively substantiated the role of BMAL1 in regulating Cyp1a2 and Cyp2e1 transcription through its binding affinity to E-box-like sites. CONCLUSION AND IMPLICATION: Our findings establish a strong link between colitis and chronopharmacology, shedding light on how IBD affects drug disposition and toxicity over time. This research provides a theoretical foundation for optimizing drug dosage in patients with IBD.

Effect of theophylline on serum and milk pharmacokinetics of tylosin following intramuscular administration in lactating goats.

AIM OF THE WORK: The study was conducted to evaluate the influence of theophylline pre-treatment on serum pharmacokinetics and milk elimination of tylosin following single intramuscular (IM) administrations in lactating goats. METHODS AND RESULTS: In a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively. CONCLUSIONS: The withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.

The complexity of coffee and its impact on metabolism.

Coffee is one of the three most consumed beverages in the world. It is made by first roasting coffee beans, and then grinding and boiling or steeping the roasted beans in water (brewing). The process of roasting and brewing produces a complex mix of bioactive compounds, including methylxanthines (caffeine, theobromine, theophylline), diterpenes, chlorogenic acid, trigonelline, flavonoids, and hydroxycinnamic acid. In the body, these compounds may be metabolized to produce other bioactive compounds. For example, caffeine is primarily (80%) broken down by demethylation to produce paraxanthine. In the post-ingestion period, levels of paraxanthine may be higher than caffeine due to its slower elimination. Hence, while paraxanthine is not found in coffee itself, it has many of the same properties as caffeine and may be a major contributor to its metabolic effects. The impacts of caffeine and paraxanthine on metabolism relate to their impact on adenosine receptors (notably the A2A receptor). It has been known for almost 100 years that intake of coffee stimulates metabolism by between 5% and 20% for at least 3 h. About half of the increase in metabolic rate after drinking coffee is due to caffeine and derivatives, but the source of the other half is unclear. There are large differences in the response to the same amount of coffee in different individuals, which may be related to caffeine clearance rates, effects of other unknown pathways, genetic polymorphism, age, sex, and body composition.

Lessons to Learn for 3D Printing of Drug Products by Semisolid Extrusion (SSE).

Semisolid extrusion (SSE) 3D printing (3DP) technology is emerging due to its simplicity and potential for on-site manufacturing of personalized drug products with tailored functionality (dose, release profile), as well as recognizability (size, shape, color). However, even a minor change in the composition of the ink (the feedstock material) and the printing process parameters can largely influence the outcome of printing. This paper summarizes the recent SSE 3DP studies, where the important factors affecting the quality of the printed drug products are discussed. Further challenges are showcased by introducing a case study focusing on the design of oral theophylline immediate-release drug products. The identified crucial factors, such as the printing hardware and connected software, printing parameters, and composition of the ink are discussed. Especially, the rheological properties of the ink during the printing process, together with solidification, mechanical properties, and morphology studies of already printed products are deliberated to gain more understanding of the printability of drug products by SSE. This work aims to provide an overview of design aspects related to SSE-based fabrication of personalized drug products.

Influence of design parameters on sustained drug release properties of 3D-printed theophylline tablets.

The application of three-dimensional printing (3DP) in the pharmaceutical industry brings a broad spectrum of benefits to patients by addressing individual needs and improve treatment success. This study investigates the sustained release properties of 3DP tablets containing Theophylline (TPH), which is commonly used to treat respiratory diseases and recently having a comeback due to its potential in the treatment of conditions like Covid-19. Since TPH is a narrow therapeutic window (NTW) drug with serious side effects in the event of overdose, the release properties must be observed particularly closely. We employed a state-of-the-art single screw extrusion 3D printer, which is fed with granules containing the drug. By employing a Taguchi orthogonal array design of experiments (DOE), tablet design parameters and factor related process stability were sought to be evaluated fundamentally. Following this, examinations regarding tailored TPH dosages were undertaken and a relationship between the real printed dose of selected tablet designs and their sustained drug release was established. The release profiles were analyzed using different mathematical model fits and compared in terms of mean dissolution times (MDT). Finally, in-vivo/in-vitro correlation (IVIVC) and physiologically based pharmacokinetic (PBPK) modeling showed that a paradigm patient group could be covered with the dosage forms produced.

A miniaturized additive-manufactured carbon black/PLA electrochemical sensor for pharmaceuticals detection.

Additive manufacturing is a technique that allows the construction of prototypes and has evolved a lot in the last 20 years, innovating industrial fabrication processes in several areas. In chemistry, additive manufacturing has been used in several functionalities, such as microfluidic analytical devices, energy storage devices, and electrochemical sensors. Theophylline and paracetamol are important pharmaceutical drugs where overdosing can cause adverse effects, such as tachycardia, seizures, and even renal failure. Therefore, this paper aims at the development of miniaturized electrochemical sensors using 3D printing and polylactic acid-based conductive carbon black commercial filament for theophylline and paracetamol detection. Electrochemical characterizations of the proposed sensor were performed to prove the functionality of the device. Morphological characterizations were carried out, in which chemical treatment could change the surface structure, causing the improvement of the analytical signal. Thus, the detection of theophylline at a linear range of 5.00-150 µmol L-1 with a limit of detection of 1.2 µmol L-1 was attained, and the detection of paracetamol at a linear range of 1.00-200 µmol L-1 with a limit of detection of 0.370 µmol L-1 was obtained, demonstrating the proposed sensor effectively detected pharmaceutical drugs.

Switchable and orthogonal gene expression control inside artificial cells by synthetic riboswitches.

Here we report two novel synthetic riboswitches that respond to ASP2905 and theophylline and function in reconstituted cell-free protein synthesis (CFPS) system. We encapsulated the CFPS system as well as DNA-templated encoding reporter genes regulated by these orthogonal riboswitches inside liposomes, and achieved switchable and orthogonal control over gene expression by external stimulation with the cognate ligands.