Doses Of Pharmaceuticals Research Articles

Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

OS03-01: Astrocyte response in rat brain is affected by pharmacologically-relevant doses of pharmaceuticals associated with neuropsychiatric/psychological adverse events

OS03-01: Astrocyte response in rat brain is affected by pharmacologically-relevant doses of pharmaceuticals associated with neuropsychiatric/psychological adverse events

Dose Calibrator Measurements in the Case of Voltage Fluctuations

Radiation dose measurements of radiopharmaceuticals and measurements of dose calibrators at different voltages and fluctuations were evaluated. Low and high doses of technetium, iodine and fluorine pharmaceuticals were measured in different voltages. The results showed that only low doses could make small and insignificant differences.

MANUFACTURING OF RADIOPHARMACEUTICAL ISOTOPES THROUGH THE LINAC 7 ACCELERATOR FOR BIOMEDICAL APPLICATIONS

Linac 7 consists of a new generation linear proton accelerator completely designed and built at the Beam Laboratory (IZPILab-Beam Laboratory) of the University of the Basque Country UPV/EHU. One of the most important health applications conceived within the Linac 7 project is the production of pharmaceuticals of various species, locally around large clinical centers. Currently, medical radioisotopes are manufactured externally to hospitals and involve the use of distant, expensive and complex infrastructures. This results in long transports, production of large doses of radioisotopes that decay rapidly over the several hours of transport, and also usually only elements with sufficient half-life for use as appropriate pharmaceuticals can be used, with no other options. Our compact Linac 7 linear accelerator allows the manufacture of multiple types of radioisotopes locally and tailored to the corresponding biomedical needs, including specific doses of pharmaceuticals for patients, on demand of the medical staff in our hospitals. Keywords: Particle accelerators, radiopharmacy, nuclear medicine

Epitranscriptomic Reprogramming Is Required to Prevent Stress and Damage from Acetaminophen

Epitranscriptomic marks, in the form of enzyme catalyzed RNA modifications, play important gene regulatory roles in response to environmental and physiological conditions. However, little is known with respect to how acute toxic doses of pharmaceuticals influence the epitranscriptome. Here we define how acetaminophen (APAP) induces epitranscriptomic reprogramming and how the writer Alkylation Repair Homolog 8 (Alkbh8) plays a key gene regulatory role in the response. Alkbh8 modifies tRNA selenocysteine (tRNASec) to translationally regulate the production of glutathione peroxidases (Gpx’s) and other selenoproteins, with Gpx enzymes known to play protective roles during APAP toxicity. We demonstrate that APAP increases toxicity and markers of damage, and decreases selenoprotein levels in Alkbh8 deficient mouse livers, when compared to wildtype. APAP also promotes large scale reprogramming of many RNA marks comprising the liver tRNA epitranscriptome including: 5-methoxycarbonylmethyluridine (mcm5U), isopentenyladenosine (i6A), pseudouridine (Ψ), and 1-methyladenosine (m1A) modifications linked to tRNASec and many other tRNA’s. Alkbh8 deficiency also leads to wide-spread epitranscriptomic dysregulation in response to APAP, demonstrating that a single writer defect can promote downstream changes to a large spectrum of RNA modifications. Our study highlights the importance of RNA modifications and translational responses to APAP, identifies writers as key modulators of stress responses in vivo and supports the idea that the epitranscriptome may play important roles in responses to pharmaceuticals.

Bisphenol S Alters the Lactating Mammary Gland and Nursing Behaviors in Mice Exposed During Pregnancy and Lactation.

High doses of estrogenic pharmaceuticals were once prescribed to women to halt lactation. Yet, the effects of low-level xenoestrogens on lactation remain poorly studied. We investigated the effects of bisphenol S (BPS), an estrogen receptor (ER) agonist, on the lactating mammary gland; the arcuate nucleus, a region of the hypothalamus important for neuroendocrine control of lactational behaviors; and nursing behavior in CD-1 mice. Female mice were exposed to vehicle, 2 or 200 µg BPS/kg/d from pregnancy day 9 until lactational day (LD) 20, and tissues were collected on LD21. Tissues were also collected from a second group at LD2. BPS exposure significantly reduced the fraction of the mammary gland comprised of lobules, the milk-producing units, on LD21, but not LD2. BPS also altered expression of Esr1 and ERα in the mammary gland at LD21, consistent with early involution. In the arcuate nucleus, no changes were observed in expression of signal transducer and activator of transcription 5, a marker of prolactin signaling, or ERα, suggesting that BPS may act directly on the mammary gland. However, observations of nursing behavior collected during the lactational period revealed stage-specific effects on both pup and maternal nursing behaviors; BPS-treated dams spent significantly more time nursing later in the lactational period, and BPS-treated pups were less likely to initiate nursing. Pup growth and development were also stunted. These data indicate that low doses of BPS can alter lactational behaviors and the maternal mammary gland. Together, they support the hypothesis that pregnancy and lactation are sensitive to low-dose xenoestrogen exposures.

Health Service Use, Costs, and Adverse Events Associated with Potentially Inappropriate Medication in Old Age in Germany: Retrospective Matched Cohort Study.

Drug-related problems are an important healthcare safety concern in the growing population of older people. Prescription of potentially inappropriate medication (PIM) is one aspect of this concern that is considered to increase the risk of adverse health outcomes. The aim of the Health Economics of Potentially Inappropriate Medication (HEPIME) study was to analyze the association between the prescription of PIMs according to the German PRISCUS list and healthcare utilization, healthcare costs, and the occurrence of adverse events in old age. Insurants of a large German health insurance company aged 65+ years were included in a retrospective matched cohort study. A total of 3,953,423 individuals with no exposure to PIM in 2011 were matched to 521,644 exposed individuals and compared in terms of outpatient healthcare utilization, healthcare costs, and the occurrence of adverse events in outpatient, hospital, and rehabilitation sectors during a 12-month follow-up. On average, individuals in the exposed group had additional 143 [95% confidence interval (CI) 140-146] daily defined doses of pharmaceuticals and 4.5 (95% CI 4.4-4.6) days in hospital. Mean annual total healthcare costs per individual in the exposed group exceeded those in the non-exposed group by €2321 (95% CI 2269-2372), resulting mainly from differences in hospitalization costs of €1718 (95% CI 1678-1759). Odds ratios for the occurrence of adverse events in the exposed group were 1.32 (95% CI 1.32-1.34) in the outpatient sector, 1.76 (95% CI 1.73-1.79) in the hospital sector, and 1.82 (95% CI 1.76-1.89) in the rehabilitation sector. Increased healthcare utilization and costs as well as an increased probability for adverse events in individuals exposed to PIM demonstrate the health economic relevance of PIM prescriptions. Whether avoiding PIM listed on the PRISCUS list may potentially improve the quality and efficiency of healthcare is currently unknown.

Diabetic peripheral angiopathy treatment using a multi-laser therapy device

Diabetic peripheral angiopathy treatment using a multi-laser therapy device

Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice

Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 106ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 106ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 102–103ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants.

Cardiac resynchronization therapy allows the optimization of medical treatment in heart failure patients

AimCardiac resynchronization therapy (CRT) is recommended for selected patients with advanced heart failure (HF) despite optimal medical treatment. However, the doses of pharmaceuticals in this population are often limited by adverse effects. We compared the drug regimens of 21 patients before and 6months after they underwent the implantation CRT systems. MethodsWe studied 17 men and four women (mean age=63.4±11years) presenting in New York Heart Association HF classes III-IV, and with a left ventricular ejection fraction (LVEF)≤35% and cardiac dyssynchrony, who underwent implantation of CRT systems. ResultsAt baseline, 52% of patients were treated with β-adrenergic blockers (β-B), though in optimal doses in only 19%. The introduction of (β-B) was complicated by cardiogenic shock in three patients. At baseline, all patients were treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), of whom 76% received optimal doses. After 6months of CRT, β-B were administered to 76% of patients, in optimaklon ACE or ARB but 75% of them were receiving maximal doses. After 6months of CRT, β blockers have been introduced in 72% of patients and maximal doses have been achieved in 60% of them. Maximal doses of ACE or ARB were reached in 95% of the study population. We noticed that systolic blood pressure was higher after implantation. There was also a significant improvement in functional status and left ventricular ejection fraction compared to baseline. ConclusionCRT is an efficacious adjunctive device therapy to standard medical therapy for patients with heart failure and cardiac dyssynchrony. Its benefits are in addition to those afforded by standard pharmacological therapy. Achieving maximal doses of medical treatment and the possibility of introducing β blockers after CRT prove that CRT and pharmacological treatment are complementary strategies and should not be considered as competitive.

An approach for the quantitative consideration of genetic polymorphism data in chemical risk assessment: examples with warfarin and parathion.

In recent years, a great deal of research has been conducted to identify genetic polymorphisms. One focus has been to characterize variability in metabolic enzyme systems that could impact internal doses of pharmaceuticals or environmental pollutants. Methods are needed for using this metabolic information to estimate the resulting variability in tissue doses associated with chemical exposure. We demonstrate here the use of physiologically based pharmacokinetic (PBPK) modeling in combination with Monte Carlo analysis to incorporate information on polymorphisms into the analysis of toxicokinetic variability. Warfarin and parathion were used as case studies to demonstrate this approach. Our results suggest that polymorphisms in the PON1 gene, that give rise to allelic variants of paraoxonase, which is involved in the metabolism of paraoxon (a metabolite of parathion), make only a minor contribution to the overall variability in paraoxon tissue dose, while polymorphisms in the CYP2C9 gene, which gives rise to allelic variants of the major metabolic enzyme for warfarin, account for a significant portion of the overall variability in (S)-warfarin tissue dose. These analyses were used to estimate chemical-specific adjustment factors (CSAFs) for the human variability in toxicokinetics for both parathion and warfarin. Implications of alternatives in the calculation of CSAFs are explored. Key decision points for applying the PBPK-Monte Carlo approach to evaluate toxicokinetic variability for other chemicals are also discussed.

Model of a biological cell exposed to extremely small doses (discussed).

This article considers the physical properties of cells. On the basis of these properties, an electrodynamic model was constructed in terms of equivalent networks. This model makes it possible to study how external influences act upon a cell. For example, it can be employed to analyze cell behavior at different doses of pharmaceuticals, alpha emission, beta radiation, gamma rays, and electromagnetic fields.