An assessment of mutagenicity, genotoxicity, acute-, subacute and subchronic oral toxicity of paraxanthine (1,7-dimethylxanthine).

Paraxanthine or 1,7-dimethylxanthine is a natural dietary component and the main metabolite of caffeine in humans. A battery of toxicological studies was conducted in accordance with international guidelines to investigate mutagenicity, genotoxicity and acute and repeated-dose oral toxicity in rats of synthetic paraxanthine (ENFINITY™, Ingenious Ingredients, L.P., >99% purity). There was no evidence of mutagenicity in a bacterial reverse mutation as well as in an in vitro mammalian chromosomal aberration test. There was no evidence of genotoxicity in an in vivo mammalian erythrocyte micronucleus test as well as in an in vitro mammalian cell gene mutation test. An acute oral toxicity test resulted in a LD50 value of 1601 mg/kg bw/d. Paraxanthine did not cause mortality or toxic effects in a subacute 28-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. Paraxanthine also did not cause mortality or toxic effects in a subchronic 90-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. The no observed adverse effect level (NOAEL) determined from the 90-day study was greater than or equal to 300 mg/kg bw/d, the highest dose tested, for both male and female Wistar rats.

Efficacy and safety of combined doxofylline and salbutamol in treatment of acute exacerbation of chronic obstructive pulmonary disease

SUMMARY OBJECTIVE: The aim of this study was to investigate the efficacy and safety of combined doxofylline and salbutamol in the treatment of acute exacerbation of chronic obstructive pulmonary disease. METHODS: A total of 68 acute exacerbation of chronic obstructive pulmonary disease patients were randomly divided into control group (34 cases) and experimental group (34 cases), who received the doxofylline treatment and combined doxofylline and salbutamol treatment for 1 week, respectively. During the treatment, the remission time of typical respiratory manifestations was recorded, and the adverse reactions were observed. At the end of treatment, the treatment efficacy was evaluated. Before and after treatment, the pulmonary function indexes and serological indicators were detected. RESULTS: After treatment, compared with control group, in experimental group, the effective rate of treatment was significantly increased (p<0.05), the remission time of typical respiratory manifestations was significantly shortened (p<0.05), the pulmonary function indexes were significantly improved (p<0.05), the serum high-sensitivity C-reactive protein and cystatin C levels were significantly decreased, respectively (p<0.05), and the serum prealbumin level was significantly increased (p<0.05). In addition, the adverse reaction rate had no significant difference between two groups (p>0.05). CONCLUSIONS: In the treatment of acute exacerbation of chronic obstructive pulmonary disease, the combined use of doxofylline and salbutamol can quickly relieve the respiratory symptoms, mitigate the pulmonary dysfunction, and reduce the inflammatory response, thus promoting the outcome of patients.

Injection-molded capsule bodies and caps based on polymer blends for controlled drug delivery.

A variety of polymer:polymer blends was used to prepare hot melt extrudates and empty capsules (bodies and caps) by injection-molding using a benchtop extruder (Babyplast). KollidonSR:inulin and Carbothane:inulin blends were investigated. The impact of the blend ratio on the water uptake and dry mass loss kinetics upon exposure to 0.1 MHCl, phosphate buffer pH6.8 and culture medium optionally inoculated with fecal samples from Inflammatory Bowel Disease (IBD) patients were studied. Hot melt extrudates were loaded with up to 60% theophylline, capsules were filled with drug powder. Increasing the inulin content led to increased water uptake and dry mass loss rates, resulting in accelerated drug release from the dosage forms, irrespective of the type of polymer blend. This can be attributed to the higher hydrophilicity/water-solubility of this polymer compared to KollidonSR and Carbothane. Interestingly, the presence of fecal samples in culture medium increased the water uptake and dry mass loss of hot melt extrudates to a certain extent, suggesting partial system degradation by bacterial enzymes. However, these phenomena did not translate into any noteworthy impact of the presence of colonic bacteria on theophylline release from the investigated extrudates or capsules. Hence, drug release can be expected to be independent of the location "small intestine vs. colon" from these dosage forms, which can be advantageous for long term release throughout the entire gastro intestinal tract.

Effect of histone acetylation on maintenance and reinstatement of morphine-induced conditioned place preference and ΔFosB expression in the nucleus accumbens and prefrontal cortex of male rats.

Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ΔFosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5 mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1 mg/kg) was administered to induce reinstatement. H4 acetylation and ΔFosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25 mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20 mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ΔFosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.

Evaluation of Physiologically Based Pharmacokinetic Models to Predict the Absorption of BCS Class I Drugs in Different Pediatric Age Groups.

Age-related changes in many parameters affecting drug absorption remain poorly characterized. The objective of this study was to apply physiologically based pharmacokinetic (PBPK) models in pediatric patients to investigate the absorption and pharmacokinetics of 4 drugs belonging to the Biopharmaceutics Classification System (BCS) class I administered as oral liquid formulations. Pediatric PBPK models built with PK-Sim/MoBi were used to predict the pharmacokinetics of acetaminophen, emtricitabine, theophylline, and zolpidem in different pediatric populations. The model performance for predicting drug absorption and pharmacokinetics was assessed by comparing the predicted absorption profile with the deconvoluted dose fraction absorbed over time and predicted with observed plasma concentration-time profiles. Sensitivity analyses were performed to analyze the effects of changes in relevant input parameters on the model output. Overall, most pharmacokinetic parameters were predicted within a 2-fold error range. The absorption profiles were generally reasonably predicted, but relatively large differences were observed for acetaminophen. Sensitivity analyses showed that the predicted absorption profile was most sensitive to changes in the gastric emptying time (GET) and the specific intestinal permeability. The drug's solubility played only a minor role. These findings confirm that gastric emptying time, more than intestinal permeability or solubility, is a key factor affecting BCS class I drug absorption in children. As gastric emptying time is prolonged in the fed state, a better understanding of the interplay between food intake and gastric emptying time in children is needed, especially in the very young in whom the (semi)fed condition is the prevailing prandial state, and hence prolonged gastric emptying time seems more plausible than the fasting state.

GLP-1 vasodilatation in humans with coronary artery disease is not adenosine mediated.

BACKGROUND: Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. METHODS: We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time-Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). RESULTS: There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G - 0.23 s (0.27) versus group GT - 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: - 20.83 mmHg s (24.54 vs. - 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine - 2.0 ng/ml (- 117.1, 14.8) versus - 0.5 ng/ml (- 19.6, 9.4); p = 0.60. CONCLUSION: The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. TRIAL REGISTRATION: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.

Methylxanthines and Neurodegenerative Diseases: An Update.

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.

Severe pallid breath-holding spells treated with low-dose theophylline.

BACKGROUND: The medical treatment for severe pallid breath-holding spells accompanied with severe bradycardia or transient cardiac arrest is controversial. Although various medications have been reported to be effective, patients treated with pacemaker insertion are not always evaluated for pharmacological therapy beforehand. CASE REPORT: A 9-month-old boy developed pallid breath-holding spells. At 15 months of age, a Holter electrocardiogram revealed 12 s of asystole during a breath-holding spell. Treatment with low-dose theophylline sustained-release dry syrup (5.3 mg/kg/day) led to complete control of the spells. The peak concentration of theophylline was 4.4 µg/mL which was below the therapeutic range for bronchial asthma. When he turned 3 years and 5 months of age, theophylline treatment was discontinued without recurrence of pallid breath-holding spells. DISCUSSION: Theophylline is now infrequently used to treat pediatric bronchial asthma due to its limited effect coupled with its side effects, which include headache, digestive symptoms, and theophylline-associated convulsions. The effectiveness of theophylline as a treatment for pallid breath-holding spells has been reported in several reports. In our case, the theophylline dosage was approximately half the amount described in previous reports. CONCLUSIONS: In this case, low-dose theophylline was adequate in controlling the pallid breath-holding spells. Because theophylline-associated seizures are a major concern, we suggest an evaluation of low-dose theophylline for treating patients with severe pallid breath-holding spells without febrile convulsions or epilepsy before proceeding with permanent pacemaker insertion. Further development of preventive strategies for theophylline-associated seizures and characterization of patients who respond well to theophylline treatment is required.

Lipotoxicity-associated inflammation is prevented by guarana (Paullinia cupana) in a model of hyperlipidemia.

Hyperlipidemia causes lipotoxicity which prompts an inflammatory response linked to the development of cardiovascular diseases. Natural compounds have been receiving special attention for its potential to treat diseases, inexpensiveness, and safety. Guarana (Paullinia cupana) has demonstrated notable anti-inflammatory and antioxidant effects, which may prevent chronic diseases caused by changes in lipid profile. Thus, this study aims to evaluate the effect of guarana powder (Paullinia cupana) in the purine metabolism and inflammatory profile in lymphocytes and serum of rats with Poloxamer-407-induced hyperlipidemia. Pretreatment with guarana 12.5, 25, and 50 mg/kg/day or caffeine (0.2 mg/kg/day) by gavage was applied to adult male Wistar rats for a period of 30 days. As a comparative standard, we used simvastatin (0.04 mg/kg) post-induction. Hyperlipidemia was acutely induced with intraperitoneally injection of Poloxamer-407 (500 mg/kg). Guarana powder and caffeine increased the activity of the E-NTPDase (ecto-apyrase), and all pretreatments decreased the E-ADA (ecto-adenosine deaminase) activity, reducing the inflammatory process caused by lipotoxicity. In hyperlipidemic rats, ATP levels were increased while adenosine levels were decreased, guarana and caffeine reverted these changes. Guarana powder, caffeine, and simvastatin also prevented the increase in INF-γ and potentiated the increase in IL-4 levels, promoting an anti-inflammatory profile. Guarana promoted a more robust effect than caffeine. Our results show that guarana powder and caffeine have an anti-inflammatory as seen by the shift from a proinflammatory to an anti-inflammatory profile. The effects of guarana were more pronounced, suggesting that guarana powder may be used as a complementary therapy to improve the lipotoxicity-associated inflammation.

Opioid-free general anesthesia and induced recovery from anesthesia in a patient with myotonic dystrophy type-1: a case report / Anestesia geral sem opioide e recuperação induzida da anestesia em paciente com distrofia miotônica tipo-1: relato de caso

Abstract Myotonic dystrophy type-1 (Steinert disease) is an autosomal dominant, progressive multisystem disease in which myotonic crisis can be triggered by several factors including pain, emotional stress, hypothermia, shivering, and mechanical or electrical stimulation. In this report, dexmedetomidine-based general anesthesia, in combination with a thoracic epidural for laparoscopic cholecystectomy in a patient with Steinert disease, is presented. An Aintree intubation catheter with the guidance of a fiberoptic bronchoscope was used for intubation to avoid laryngoscopy. Prolonged anesthetic effects of propofol were reversed, and recovery from anesthesia was accelerated using an intravenous infusion of theophylline.

Resumo A Distrofia Miotônica (DM) tipo-1 (Doença de Steinert) é uma doença multissistêmica progressiva autossômica dominante em que a crise miotônica pode ser desencadeada por vários fatores, incluindo dor, estresse emocional, hipotermia, tremores e estímulo mecânico ou elétrico. O presente relato descreve anestesia geral realizada com dexmedetomidina em combinação com peridural torácica para colecistectomia laparoscópica em paciente com Doença de Steinert. Para evitar laringoscopia, a intubação traqueal foi realizada utilizando cateter de intubação Aintree guiado por broncofibroscopia óptica. Os efeitos anestésicos prolongados do propofol foram revertidos e a recuperação anestésica foi acelerada pelo uso de infusão intravenosa de teofilina.

[Opioid-free general anesthesia and induced recovery from anesthesia in a patient with myotonic dystrophy type-1: a case report]. / Anestesia geral sem opioide e recuperação induzida da anestesia em paciente com distrofia miotônica tipo­1: relato de caso.

Myotonic dystrophy type-1 (Steinert disease) is an autosomal dominant, progressive multisystem disease in which myotonic crisis can be triggered by several factors including pain, emotional stress, hypothermia, shivering, and mechanical or electrical stimulation. In this report, dexmedetomidine-based general anesthesia, in combination with a thoracic epidural for laparoscopic cholecystectomy in a patient with Steinert disease, is presented. An Aintree intubation catheter with the guidance of a fiberoptic bronchoscope was used for intubation to avoid laryngoscopy. Prolonged anesthetic effects of propofol were reversed, and recovery from anesthesia was accelerated using an intravenous infusion of theophylline.

Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

BACKGROUND: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies. METHODS: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined. RESULTS: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates. CONCLUSIONS: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population. IMPACT: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.

Well-tempered MCMC simulations for population pharmacokinetic models.

A full Bayesian statistical treatment of complex pharmacokinetic or pharmacodynamic models, in particular in a population context, gives access to powerful inference, including on model structure. Markov Chain Monte Carlo (MCMC) samplers are typically used to estimate the joint posterior parameter distribution of interest. Among MCMC samplers, the simulated tempering algorithm (TMCMC) has a number of advantages: it can sample from sharp multi-modal posteriors; it provides insight into identifiability issues useful for model simplification; it can be used to compute accurate Bayes factors for model choice; the simulated Markov chains mix quickly and have assured convergence in certain conditions. The main challenge when implementing this approach is to find an adequate scale of auxiliary inverse temperatures (perks) and associated scaling constants. We solved that problem by adaptive stochastic optimization and describe our implementation of TMCMC sampling in the GNU MCSim software. Once a grid of perks is obtained, it is easy to perform posterior-tempered MCMC sampling or likelihood-tempered MCMC (thermodynamic integration, which bridges the joint prior and the posterior parameter distributions, with assured convergence of a single sampling chain). We compare TMCMC to other samplers and demonstrate its efficient sampling of multi-modal posteriors and calculation of Bayes factors in two stylized case-studies and two realistic population pharmacokinetic inference problems, one of them involving a large PBPK model.

Lung Health Care pilot project trims patient pill load and antibiotic prescription in primary health care settings in Kerala, India.

INTRODUCTION: Kerala, the southern Indian state piloted Lung Health Care Project (LHCP) which is a locally adopted version of WHO recommended Practical Approach to Lung health (PAL). The current study assessed the impact of the project on the prescribing practices of doctors and consumption of antibiotics and other drugs. METHODS: This study compared performance of primary health care institutions with regard to drug prescriptions and consumptions before and after the implementation of the project. Chronic respiratory disease (CRD) patients in institutions implemented the project were interviewed in the OPD at exit and their prescriptions were documented at baseline and after six months. Focus group discussions were conducted with doctors to explore the reasons behind changes in drug consumption pattern. RESULTS: In the project implementing institutions, mean number of drugs prescribed for CRDs was 3.88 (SD 1.50) and 2.73 (SD 1.18) at baseline and after six months respectively (p < 0.001). Adjusted odds ratio for prescribing an antibiotic and injection to a CRD patient during impact assessment at institutions implementing project was 0.34 (95% CI 0.15-0.75 p 0.008) and 0.39 (95% CI 0.20-0.74 p 0.004) respectively, as compared to baseline. The factors which helped in reducing antibiotic and injection use as felt by the doctors were presence of a protocol, good quality trainings, supportive supervision and monitoring, availability of alternate drugs and good participation of staff nurses especially in-patient education. CONCLUSION: Strict adherence to diagnostic and management algorithms of Lung health care project in a primary health care setting in India helped in reducing pill burden to patients and prescription of antibiotics and injections.

Caffeine for the Treatment of Apnea in the Neonatal Intensive Care Unit: A Systematic Overview of Meta-Analyses.

BACKGROUND: Caffeine is a common treatment for neonatal intensive care management of the developmental complication of apnea of prematurity in preterm infants. There are several systematic reviews (SRs) on the performance of caffeine in the treatment of apnea. The evidence provided by those, however, is depressed by an information overload due to high heterogeneity in the characteristics as well as the quality of these SRs. OBJECTIVE: The aim was to provide a systematic overview of SRs on the use of caffeine for the management of neonatal apnea. Such overviews are a recent method used to assess and filter top evidence among SRs, enabling enhanced access to targeted information of interest. METHODS: A comprehensive literature search was conducted via EMBASE, Cochrane Database of Systematic Reviews (CDSR), and PubMed since inception to January 2020. Two reviewers independently conducted study selection and data extraction, and assessed the quality of methods and the risk of bias in included SRs based on A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) and Risk of Bias in Systematic Reviews (ROBIS) tools. Extracted data related to study type, characteristics, patients, intervention, comparator, regimen, and outcome measures. RESULTS: Seven SRs with meta-analyses (SRMAs) were included in the current overview, involving a total of 63,315 neonates. SRMAs included randomized clinical and observational studies, with various types of patients, comparators, and outcomes. The quality of SRMAs ranged from critically low (n = 1), low (n = 1), moderate (n = 2), to high (n = 3), and the risk of bias was unclear (n = 2), low (n = 4), and high (n = 1). The effectiveness of caffeine with regard to treatment success and the rate of apnea was not significantly different from that of theophylline or doxapram in two SRMAs. Against control, in one SRMA, while caffeine reduced the rate of failure as well as the need for pressure ventilation, it did not significantly reduce mortality. This comparative effectiveness of caffeine was based on high-quality SRMAs with a low risk of bias. The effectiveness against apnea seems to be enhanced via the administration of early (0-2 days) or high doses of caffeine in one and three SRMAs, respectively. This, nevertheless, was based on lower-quality SRMAs with a higher risk of bias. Safety outcomes were mostly based on comparative SRMAs of different drug regimens, whereby, less tachycardia and lower risk for complications were reported with lower and earlier caffeine administrations, respectively. The evidence behind this, however, was limited in quantity and quality. CONCLUSION: While limited in quantity, there is evidence of non-inferior effectiveness of caffeine against other methylxanthines or doxapram for the management of apnea in neonates. Owing to the limited quality, however, limited evidence exists in support of an optimal administration regimen for caffeine. Further controlled studies are, therefore, needed to confirm the comparative usefulness of caffeine as well as to assess its different potential regimens, including in relation to safety.

A novel natural GRAS-grade enteric coating for pharmaceutical and nutraceutical products.

In this study, enteric coatings based exclusively on naturally occurring ingredients were reported. Alginate (Alg) and pectin (Pec) blends with or without naturally occurring glyceride, glycerol monostearate (GMS), were initially used to produce solvent-casted films. Incorporating GMS in the natural polymeric films significantly enhanced the acid-resistance properties in gastric medium. Theophylline tablets coated with Alg-Pec blends without GMS disintegrated shortly after incubation in gastric medium (pH 1.2), leading to a premature and complete release of theophylline. Interestingly, tablets coated with Alg-Pec blends that contain the natural glyceride (GMS) resisted the gastric environment for 2 h with minimal drug release (<5%) and disintegrated rapidly following introduction to the intestinal medium, allowing a fast and complete drug release. Furthermore, the coating system proved to be stable for six months under accelerated conditions. These findings are particularly appealing to nutraceutical industry as they provide the foundation to produce naturally-occurring GRAS based enteric coatings.

Investigating the Role of Altered Systemic Albumin Concentration on the Disposition of Theophylline in Adult and Pediatric Patients with Asthma by Using the Physiologically Based Pharmacokinetic Approach.

Theophylline is commonly used for the treatment of asthma and has a low hepatic clearance. The changes in plasma albumin concentration occurring in asthma may affect the exposure of theophylline. The aim of the presented work was to predict theophylline pharmacokinetics (PK) after incorporating the changes in plasma albumin concentration occurring in patients with asthma into a physiologically based pharmacokinetic (PBPK) model to see whether these changes can affect the systemic theophylline concentrations in asthma. The PBPK model was developed following a systematic model building approach using Simcyp. The predictions were performed initially in healthy adults after intravenous and oral drug administration. Only when the developed adult PBPK model had adequately predicted theophylline PK in healthy adults, the changes in plasma albumin concentrations were incorporated into the model for predicting drug exposure in patients with asthma. After evaluation of the developed model in the adult population, it was scaled to children on physiologic basis. The model evaluation was performed by using visual predictive checks and comparison of ratio of observed and predicted (Robs/Pre) PK parameters along with their 2-fold error range. The developed PBPK model has effectively described theophylline PK in both healthy and diseased populations, as Robs/Pre for all the PK parameters were within the 2-fold error limit. The predictions in patients with asthma showed that there were no significant changes in PK parameters after incorporating the changes in serum albumin concentration. The mechanistic nature of the developed asthma-PBPK model can facilitate its extension to other drugs. SIGNIFICANCE STATEMENT: Exposure of a low hepatic clearance drug like theophylline may be susceptible to plasma albumin concentration changes that occur in asthma. These changes in systemic albumin concentrations can be incorporated into a physiologically based pharmacokinetic model to predict theophylline pharmacokinetics in adult and pediatric asthma populations. The presented work is focused on predicting theophylline absorption, distribution, metabolism, and elimination in adult and pediatric asthma populations after incorporating reported changes in serum albumin concentrations to see their impact on the systemic theophylline concentrations.

Preparation and characterization of a powder manufactured by spray drying milk based formulations for the delivery of theophylline for pediatric use.

The study considered different fat content cow milks to deliver theophylline orally. Powders were obtained by spray drying theophylline dispersed in fresh milk according to a full factorial design of experiments. The correlation of the independent (milk fat content, skimmed to whole milk, theophylline fraction, and drying temperature) with the dependent (yield of the process and residual moisture content of the powder, particle size and distribution, density, surface polarity and theophylline content) variables enabled the construction of a mathematical model and a desirability function to predict the optimized levels of the variables. Good predictability was achieved for density, fairly good for yield, moisture content, surface polarity and yield whereas theophylline content and particle size were poorly predicted. Powders with up to 60% theophylline presented spherical (3.7 µm) and narrow sized distribution particles, with high density (1.6 g/cm-3) in high yields (>70%), stable for 6 month (25 °C/65%RH) in a closed container and for no longer than 2 day, after reconstitution in water due to bacteria growth (no pathogens) without signs of crystallinity. Preparations obtained with low fat milk were less stable than high fat content milk. Therefore, fresh milk can be transformed into stable powder compositions to prepare oral solid/liquid dosage forms to deliver individualized doses of theophylline.

Theophylline Acetaldehyde as the Initial Product in Doxophylline Metabolism in Human Liver.

Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO's metabolism and disposition affect its antiasthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metabolism of DOXO began with a cytochrome P450 (P450)-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-P450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human. SIGNIFICANCE STATEMENT: We systematically characterized doxophylline metabolism using in vitro and in vivo assays. Our findings evolved the understandings of metabolic sites and pathways for methylxanthine derivatives with the aldehyde functional group.

Investigations of the Influences of Processing Conditions on the Properties of Spray Dried Chitosan-Tripolyphosphate Particles loaded with Theophylline.

The preparation of chitosan-tripolyphosphate (chitosan-TPP) particles by the spray drying had been reported word widely for a sustained release of drugs to prevent rapid drug metabolism. Although the spray drying is a straightforward procedure turning a liquid feed into a well-defined dry powder, seldom research works were focusing on how the processing parameters and liquid feeding constitutions of spray drying system might affect the properties of spray-dried chitosan particles loaded with drugs, such as the particle size and morphologies, which would be very important to drug encapsulation and dissolution of the drug delivery design. This study thus prepared the chitosan particles with theophylline (TH) loaded as a model drug and TPP as cross-linker at various spray drying conditions. Our results indicate the diameter of the TH/chitosan-TPP particles made by customized spray drying apparatus spans from 424 to 497 nm with a geometric standard deviation of less than 2. The corresponding release of TH was tunable by the chitosan-TPP matrix density under the selected spray drying temperature and the carrying air flow rate. These results suggest an indeed need for optimized spray drying processing conditions to make the ideal spray-dried TH/chitosan-TPP particles for the desired drug delivery.