Maximum Daily Dose Research Articles

Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer.

This new drug application was first submitted to the US Food and Drug Administration (FDA) by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999. Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the "wearing-off" phenomenon). The drug indication is for Parkinson's disease as an adjunct therapy to levodopa/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone. It is rapidly absorbed after oral administration of a single dose, with peak time generally reached within 1 hour. It is noted that no accumulation of plasma entacapone was detected after 8 daily doses. The maximum daily dose is 2000 mg. In this paper, the clinical pharmacology review of the drug is presented from the perspective of a clinical pharmacologist who reviewed this new drug application at the FDA. It should be noted that all the information in this paper is publicly available on the FDA website and in its literature.

Efficacy of Oral Steroids for Acute Acoustic Trauma

Objective: This study aimed to study the effect of steroid treatment on new-onset sensorineural hearing loss (SNHL) in subjects presenting shortly after an audiometry-confirmed acute acoustic trauma (AAT) injury. Study Design: This is a case-control study. Methods: We identified healthy military personnel who presented with AAT injury to the Israeli Defense Forces Medical Corps Otolaryngology/Audiology Services during 2016–2020. Patients were nonrandomly allocated to a treatment arm, where they received steroids (prednisone, 1 mg/kg, 60 mg maximal daily dose), administered for either ≥7 days or <7 days, or to a control arm, in which no treatment was offered besides loud noise avoidance. Audiometries were conducted within 7 days following the AAT and within 1 month later. We compared changes in bone conduction (BC) and air conduction (AC) thresholds at 2–8 kHz. Results: Of the 263 enrolled subjects, 137 (52%) received steroids and 126 (48%) received no treatment. Subjects who were treated early (<24 h) with high-dose steroids and for ≥7 days demonstrated significantly better hearing outcomes, compared with the nontreatment group. Subjects in the steroids group demonstrated 13–14 dB average improvement in BC thresholds at 3 and 4 kHz (p = 0.001) and additional 7–8 dB average improvement in AC thresholds at 6 and 8 kHz, compared with the nontreatment group (p < 0.0001). These observations were more compelling in patients who initially presented with worse hearing losses (>35 dB). No statistically significant differences were observed in AC/BC pure tone average between the two groups. Conclusions: Early oral steroids are recommended in AAT injuries and were shown to improve hearing outcomes within 1 month.

Exposures to FD&C synthetic color additives from over-the-counter medications and vitamins in United States children and pregnant women

BackgroundFood and Drug Administration (FDA) Food Drug and Cosmetic (FD&C) synthetic color additives (SCAs) have been associated with attentional and behavioral problems in children. Efforts to quantify exposure have focused on foods, while the contribution of medications and supplements remains unknown.ObjectiveTo estimate exposures to SCAs in children (2–16 years) and pregnant women from intake of common over-the-counter (OTC) medications and vitamins.MethodsWe estimated single-day exposure (mg/kg/day) to FD&C SCAs based on measurements of 25 different products and recommended dosages on product labels. Exposures were compared to SCA exposure estimates from food we previously developed and acceptable daily intakes (ADIs) established by FDA and the World Health Organization.ResultsThe highest exposure was found for FD&C Red No. 40 in a children’s cold/cough/allergy syrup. A child aged 12–16 years consuming the maximum daily dosage would have an exposure of 0.221 mg/kg/day, which is twice this age group’s typical exposure to this additive from food. No estimated exposures exceeded the ADIs.SignificanceSome children’s OTC medications and vitamins may cause daily SCA exposures comparable to those from foods. OTC medications and vitamins should be considered in efforts to quantify population exposure to FD&C SCAs.ImpactExposure to synthetic color additives (SCAs) from foods has been associated with behavioral problems in children. Exposures from over-the-counter (OTC) medications and vitamins remain unquantified despite widespread use. We estimated exposures in children and pregnant women for 25 different OTC medication and vitamin products sold in the United States. While exposures were below acceptable daily intakes (ADIs) established by the US Food and Drug Administration and the World Health Organization, some were comparable to typical daily exposures from foods. This work critically informs future SCA exposure assessments and provides valuable information for parents concerned about the health effects of SCAs.

Prospective, randomized, controlled, double-blind, multi-center, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery: study protocol for the PHOENICS study

BackgroundHydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss and to maintain hemodynamic stability. This study was requested by the European Medicines Agency (EMA) to provide more evidence on the long-term safety and efficacy of HES solutions in the perioperative setting.MethodsPHOENICS is a randomized, controlled, double-blind, multi-center, multinational phase IV (IIIb) study with two parallel groups to investigate non-inferiority regarding the safety of a 6% HES 130 solution (Volulyte 6%, Fresenius Kabi, Germany) compared with a crystalloid solution (Ionolyte, Fresenius Kabi, Germany) for infusion in patients with acute blood loss during elective abdominal surgery. A total of 2280 eligible patients (male and female patients willing to participate, with expected blood loss ≥ 500 ml, aged > 40 and ≤ 85 years, and ASA Physical status II–III) are randomly assigned to receive either HES or crystalloid solution for the treatment of hypovolemia due to surgery-induced acute blood loss in hospitals in up to 11 European countries. The dosing of investigational products (IP) is individualized to patients’ volume needs and guided by a volume algorithm. Patients are treated with IP for maximally 24 h or until the maximum daily dose of 30 ml/kg body weight is reached.The primary endpoint is the treatment group mean difference in the change from the pre-operative baseline value in cystatin-C-based estimated glomerular filtration rate (eGFR), to the eGFR value calculated from the highest cystatin-C level measured during post-operative days 1-3. Further safety and efficacy parameters include, e.g., combined mortality/major post-operative complications until day 90, renal function, coagulation, inflammation, hemodynamic variables, hospital length of stay, major post-operative complications, and 28-day, 90-day, and 1-year mortality.DiscussionThe study will provide important information on the long-term safety and efficacy of HES 130/0.4 when administered according to the approved European product information. The results will be relevant for volume therapy of surgical patients.Trial registrationEudraCT 2016-002162-30. ClinicalTrials.govNCT03278548

The era of fake medicines: Investigating counterfeit medicinal products for erectile dysfunction disguised as herbal supplements

Sales of substandard and falsified medical products (SF) are rising rapidly everywhere around the globe. The wide and easy access to these products is an alarming issue to the global health systems and undermined the health of patients, especially with the thrive of online commerce. To tackle this threat to public health, new ways to access these products should be identified and detection technologies should be strengthened. The overarching aim of this study was to investigate if herbal supplements sold online claiming to be natural alternatives to Viagra® were amongst these SF medical products and how effective different analytical techniques are in providing information about these products. 3 products which claimed to be herbal supplements for men sexual performance were purchased from an e-commerce platform. Two products were received as unregistered generic sildenafil citrate tablets manufactured in India (and thus different to the products information on the website) while one product was received in the same packaging as shown on the website, claiming to be an herbal product. Nevertheless, all products were proven to contain sildenafil citrate, the active pharmaceutical ingredients in Viagra® after the comprehensive analytical tests. The results elucidated that the quality standards for the unregistered generic sildenafil citrate tablets were fulfilled according to the British Pharmacopeia, but the falsified product failed the quality tests and contained approximately 200 mg sildenafil citrate, which is equivalent to 2-fold of the daily maximum dose. Furthermore, physical characterisations, including powder x-ray diffraction and thermal analysis were performed and revealed that the polymorphic forms of sildenafil citrate were different, demonstrating the importance of employing thermal analysis in addition to the conventional analysis techniques for the substandard and falsified medical products. These techniques provided valuable insights into the physical form of the active ingredient in these products. What is more, the ease with which these SF products were obtained and confirmed to be misleading consumers emphasises the need for tighter regulation for e-commerce websites in line with those enforced on online pharmacies.

When to Use Amisulpride in Adolescents: A Retrospective Chart Examination of Inpatients.

Despite increasing interest in amisulpride, current knowledge about its use in the pediatric population is scarce. This chart review aimed to investigate the use of amisulpride in a naturalistic adolescent population. Electronic medical records of a tertiary care adolescent inpatient unit were screened between January 2015 and April 2021. Sociodemographic data and all clinical information were collected via data collection forms, and targeted symptoms were obtained from patients' files. Patients with early-onset psychotic disorders (n = 58), bipolar I disorder (n = 29), major depressive disorder (n = 14), and other psychiatric diagnoses (n = 9) were included. Treatment response was defined as a Clinical Global Impression-Improvement of at least much improvement after treatment. Median titration rate of amisulpride was 400 mg/wk, and the maximum administered daily dose ranged between 100 and 1200 mg/d. The maximum daily dose and number of previous antipsychotics were higher in the early-onset psychotic disorder group. Persistent positive symptoms and resistance to previous treatments were leading causes for amisulpride treatment. Other indications were also impulsive/disruptive behaviors, antipsychotic adverse effects, depressive symptoms, somatic complaints, and abnormalities in liver function tests. Finally, patients with lower daily treatment doses and more previous antipsychotic trials are less likely to benefit from the treatment. Persistent psychotic/mood symptoms, impulsive/disruptive behaviors, and abnormalities in liver function tests were reasons for the amisulpride treatment in adolescents. Randomized placebo-controlled trials are needed to evaluate the efficacy and safety of the treatment in adolescents.

The Evaluation of Meropenem Dosing Regimens Against ESBL-Producing Escherichia coli in ICU Patients Using Monte Carlo Simulation.

PurposeTo evaluate the optimal dosing regimens of meropenem against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL E. coli) in critically ill patients with varying degrees of renal function using Monte Carlo simulation (MCS).MethodsThe MCS was performed using the minimum inhibitory concentration (MIC) data from Right Laboratory and Health Screen in Naypyitaw, Myanmar, as well as reported meropenem pharmacokinetic parameters in the target population and the pharmacokinetic-pharmacodynamic index. For each dosing regimen, 10,000 virtual patients were generated to assess the probability of target attainment (PTA) and the cumulative fraction of response (CFR). The most effective dosage regimens were determined using PTA and a CFR of 90%.ResultsESBL E. coli made up 93 of the 396 clinical E. coli isolates, and they are all multidrug-resistant, with resistance to at least five antibiotic classes. The MIC50 and MIC90 were determined to be 0.25 μg/mL. The PTA was affected by five factors: creatinine clearance (CLcr), vasopressor usage, MIC, infusion time, and dosage fractionation. In patients who did not receive vasopressors, the current regimens (US-FDA and EMA) were ineffective in all renal function for MIC >0.25μg/mL. In the subset group of CLcr >80 mL/min for MIC 2μg/mL, the maximum total daily dose of 6g/day (2g q 8hr; 3hr infusion) was still ineffective, but 4g/day (1g q 6hr; 3hr infusion) achieved 98.96% PTA. Almost majority of the simulated regimens produced >90% PTA in vasopressor-dependent patients with all levels of renal function, resulting in a decreased total daily dose requirement.ConclusionFor high MIC (>1μg/mL) patients who do not use vasopressors and have a CLcr >80 mL/min, a combination of dosage fractionation and the extended infusion was considered as an effective technique to maximize target attainment. Neither prolonged infusion nor dosage fractionation should be explored in patients using vasopressors.

An anchored simulated treatment comparison of uptitration of amlodipine compared with a low-dose combination treatment with amlodipine 5 mg/bisoprolol 5 mg for patients with hypertension suboptimally controlled by amlodipine 5 mg monotherapy

Objective To compare changes in systolic and diastolic blood pressures (SBP, DBP) from baseline to following 8 weeks of treatment with a low dose combination of amlodipine 5 mg plus bisoprolol 5 mg versus up titration to the maximum daily dose of amlodipine 10 mg, in hypertensive patients uncontrolled by amlodipine 5 mg. Methods Individual patient data (IPD) from a randomized clinical trial (RCT) comparing the combination versus amlodipine 5 mg (EudraCT Number: 2019-000751-13) and aggregated data (AgD) from a published RCT comparing amlodipine 10 mg versus amlodipine 5 mg were utilized in an anchored simulated treatment comparison (STC). The RCT with IPD was used to create models assessing how patients might respond to the combination if they were more comparable to those patients in the RCT with AgD. A population-adjusted indirect comparison of the treatment strategies was then conducted, using amlodipine 5 mg as an anchor. Results In the efficacy analyses, a total of 261 patients were included in the amlodipine 10 mg arm of the RCT with AgD; and a total of 178 patients in the low-dose combination arm of the RCT with IPD. Respectively, in the Amlodipine 10 mg arm and in the low-dose combination arm, the mean age was 54.3 years-old (Standard deviation [SD] 10.6), and 57.1 years-old (13.7); 8.7% and 18.8% of patients were diabetics; and the mean baseline SBP/DBP was 149.3 (12.0)/96.5 (4.7) mmHg, and 148.8 (8.2)/90.2 (7.6) mmHg. The final model for SBP and DBP included the following variables: baseline SBP, baseline DBP, duration of hypertension, age, concomitant diabetes, sex, smoking history (final model for SBP only), and body mass index (final model for DBP only). Mean treatment differences (standard error [SE]) at 8 weeks between the combination and uptitration were −1.6 mmHg (1.9) for SBP; and −3.3 mmHg (1.3) for DBP. Conclusion In this indirect comparison, a more important decrease was observed in DBP with the low-dose combination as compared to the alternative therapeutic approach of up-titration from amlodipine 5 mg to amlodipine 10 mg. No meaningful difference was seen for SBP.

A study on high-dose dexamethasone versus prednisolone as frontline therapy in newly diagnosed immune thrombocytopenia in children

Objectives: Treatment for children with newly diagnosed immune thrombocytopenia (ITP) includes corticosteroids, out of which prednisolone is commonly used. High-dose dexamethasone (HD-DXM) treatment for children with newly diagnosed ITP can produce better outcomes than prednisone, as stated by many studies. A few articles compare HD-DXM and prednisolone as frontline therapies in newly diagnosed adult ITP but data on pediatric ITP comparing these two drugs are scarce. Material and Methods: It was a randomized, prospective, and cohort study. After enrolment, checking the inclusion and exclusion criteria, each child was randomly distributed into two groups; one cohort was treated with HD-DXM in the dose of 40 mg/m2 (maximum daily dose 40 mg) for 4 days once every 28 days for three cycles; and one with prednisolone in the dose of 2 mg/kg/day (maximum 60 mg/day) for 2 weeks, with quick tapering. A total of 42 children were enrolled, 21 in each cohort. Results: The overall response (OR) was 42.9% with HD-DXM therapy. The OR and median time to response were similar in both HD-DXM and prednisolone cohorts. There was also no significant difference in incidences of adverse effects between the two cohorts. Conclusion: Thus, this study confirms that HD-DXM is a safe, effective, and non-inferior option compared to prednisolone as frontline therapy in newly diagnosed ITP in children.

Prediction model of acute kidney injury induced by cisplatin in older adults using a machine learning algorithm.

BackgroundEarly detection and prediction of cisplatin-induced acute kidney injury (Cis-AKI) are essential for the management of patients on chemotherapy with cisplatin. This study aimed to evaluate the performance of a prediction model for Cis-AKI.MethodsJapanese patients, who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital, were enrolled in the study. The main metrics for evaluating the machine learning model were the area under the curve (AUC), accuracy, precision, recall, and F-measure. In addition, the rank of contribution as a predictive factor of Cis-AKI was determined by machine learning.ResultsA total of 1,014 and 226 patients were assigned to the development and validation data groups, respectively. The current prediction model showed the highest performance in patients 65 years old and above (AUC: 0.78, accuracy: 0.77, precision: 0.38, recall: 0.70, F-measure: 0.49). The maximum daily cisplatin dose and serum albumin levels contributed the most to the prediction of Cis-AKI.ConclusionOur prediction model for Cis-AKI performed effectively in older patients.

Nefopam prescribing preferences in French hospitals: results of a survey.

Introductionnefopam is a non-opioid, centrally-acting analgesic, frequently prescribed in France for acute pain and postoperatively. Only intravenous (IV) formulation is available, however the off-label oral use is frequent in surgical and medical patients. There is no data on the actual in-hospital prescription preferences in French physicians regarding nefopam. We wish to identify nefopam prescription habits for acute and chronic pain among hospital physicians.Methodsan online survey was sent to physicians via professional emails. Frequency of prescription, indication, preferred and prescribed administration route, dose regimen, and personal perception of the nefopam tolerance and efficiency were examined.Resultsa total of 527 responses were analysed. Nefopam was mostly prescribed by senior hospital physicians, for acute pain, orally (85%), 20 mg/6h with 120 mg maximal daily dose. For chronic pain, the oral administration was more frequent. More than half of prescribers considered the efficacy of the oral route was similar to intravenous, and better tolerated compared to intravenous administration. Forty-eight percent of responders would change their prescription attitude in case of oral route approval of nefopam.Conclusionoral prescription of intravenous formulation of nefopam is frequent, especially for acute pain, and has the same dose and regimen pattern as for intravenous route. Prescribers consider oral nefopam efficient and safe for patients. Regulatory actions regarding the oral nefopam prescription authorization and duration of such prescription are needed.

Study of embryotoxic and teratogenic properties of Medicine No. 60 and evaluation of its effect on the reproductive function of rats.

Intramuscular administration of medicine No. 60 at a dose of 1.281 mg/kg (30 times the estimated highest daily dose for humans) when diluted with 1:5 saline solution to pregnant rats from Day 1 to Day 19 of pregnancy does not affect the indicators of pre- and postimplantation death of baby rats. The body weight of the rats exposed to the medicine No. 60 during the prenatal period of development did not differ from the indicators in the control group. The development of offspring in the experimental group during the entire observation period took place without deviation from the terms characteristic of the normal physiological development of animals of this species. As a result of the studies conducted, it was found that intramuscular administration of drug No. 60 at a dose of 1.281 mg/kg in a 1:10 dilution with saline solution, which was 30 times the estimated maximum daily therapeutic dose for humans, did not affect the sexual activity of animals, reproductive indicators (number of live fetuses, body weight of embryos, their craniocaudal size, number of yellow bodies, implantation sites, resorption), or the neonatal development of baby rats. Thus, there was no effect of medicine No. 60 in the test dose of 1.281 mg/kg on the reproductive function of healthy mature rats and does not exhibit embryotoxic and teratogenic activity.

ENZYMATIC ACTIVITY OF THE DEHYDROGENASE AND OXIDASE FORMS OF XANTHINOXIDASE IN THE LIVER OF RATS UNDER THE CONDITIONS OF ω-3 POLYNUNSATURATED FATTY ACIDS AND RETINOIDS

The effect of retinoid different doses in a complex with ω-3 polyunsaturated fatty acids (PUFA) on the enzyme activity of dehydrogenase (D-form – xanthine:NAD+-oxidoreductase, EC 1.17.1.4)) and oxidase (O-form – xanthine: oxygen oxidoreductase, EC 1.17.3.2) isoforms of xanthine oxidase and the generation of superoxide radical (O2•-) in the liver cytosolic fraction of rat are studied. Animals were divided into four groups: I – intact animals (control); II – rats injected with ω-3 PUFA at a dose of 120 mg/kg of animal weight; III, IV, V – animals administered retinol acetate at a dose of 60 IU/kg, 600 IU/kg, 1800 IU/kg, respectively; VI, VII, VIII – rats that were injected with a complex of ω-3 PUFAs and retinol acetate in doses of 60 IU/kg, 600 IU/kg, and 1800 IU/kg, respectively. Euthanasia of animals was performed under light ether anesthesia on the 14th day after the start of drug administration. It was established in-crease in total xanthine oxidase activity by 2.5 and 2.7 times compared to the values of the group of intact animals under the administering of a therapeutic dose of 600 IU/kg of retinol acetate and a maximum daily dose of 1800 IU/kg, respectively. The combined use of ω-3 PUFA and retinol acetate in doses of 600 IU/kg and 1800 IU/kg led to a decrease in the total xanthine oxidase activity in comparison with the values of animals that were administered the retinol acetate preparation separately in the corresponding doses. It is shown that the increase in the total activity of xanthine oxidase occurs due to the increase in the activity level of its O-form with a simultaneous decrease in the activity of the D-form. An increase of O-form xanthine oxidase activity in the liver cytosolic fraction the occurs in parallel with an increase in the rate of O2•- formation. This indicates the participation of this isoform in the induction of redox imbalance in the cytosol of liver cells under the influence of high doses of retinol acetate. The use of ω-3 PUFA along with retinol acetate contributes to the studied indicators normalization.

High levels of benzodiazepines after treatment of moderate alcohol withdrawal syndrome: the problem of incomplete detoxification.

Some alcohol-dependence relapses occur soon after a concluded detoxification treatment. A popular agent used in that treatment is diazepam, which effectively relieves withdrawal symptoms due to its long half-life and affinity to the same receptors. It is hypothesized here that these attributes, after nominally completed detoxification, result in, respectively, persisting benzodiazepine (BZD) influence and a distorted (optimistic) clinical presentation. This could contribute to later reemergence of withdrawal symptoms caused by delayed final elimination of BZDs, as the evidence puts into doubt the concept of a gentle self-taper of a long-acting drug. Serum-BZD concentration levels were measured with a radioimmunoassay at the end of routine treatment of moderately- intense alcohol withdrawal syndrome. These data were cross-referenced with individual diazepam administration schedules, including the maximal daily dose and the day of its administration, and the day of overall diazepam cessation. Most patients revealed clinically relevant serum-BZD levels. These correlated with the doses but also with the day of maximal- dose administration and the day of diazepam withdrawal. The confrontation with actual abstinence comes after detoxification. Delayed elimination of diazepam may be a contributing factor in the re-emergence of symptoms and early post-detox relapses. The optimization of the procedure has been discussed in terms of concentration evolution and known treatment schedules. Maximal initial dosage compression and further decisive counteracting the tendencies of diazepam towards accumulation increase the patient's chance of going through the low-concentration crisis under medical assistance.

Sensitive and Selective Analytical Method for the Quantification of Two Potential Genotoxic Impurities in Azilsartan Drug Substance by using LC-MS/MS with Multiple Reaction Monitoring (MRM mode)

The main aim of the present study to Synthesize,method development and method validation for quantification of two potential genotoxic impurities i.e., Methyl(Z)-2-ethoxy-1-((2'-(N'-hydroxycarbamimidoyl)-[1,1'-biphenyl]-4-yl) methyl)-1H-benzo[d]imidazole-7-carboxylate(Impurity-A) and 2-ethoxy-1-((2'-(N'-hydroxycarbamimidoyl[)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid(Impurity-B) by using LC-MS/MS MRM mode at trace level determination inAzilsartan drug substance. The new LC-MS/MS MRM mode method was developed by using Inertsil ODS-3V 150x4.6mm,5µm column as stationary phase. The mobile phase used is the composition of 10Mm Ammonium formate pH3.00buffer:Acetonitrile(9:1)%v/v as mobilephase-A and 10Mm Ammonium formate pH3.00buffer:Acetonitrile(2:8)%v/v as mobile phase-B, isocratic elution of mobile phase-A and Mobile phase-B (60:40)v/v at flow rate of 0.8mL/min.The concentration limits of the both genotoxic impurities were calculated a limit of 37.5ppm based on the concept of TTC (threshold of toxicological concern) and MDD (maximum daily dosage which is 40mg/day for Azilsartan drug substance.The limit of detection(LOD) was found to be 1.4ppm for both Impurity-A and Impurity-B.The limit of quantification(LOQ) for Impurity-A was 4.7ppm and Impurity-B was 4.5ppm respectively The method was found to be linear from 4.7ppm to 78.4ppm for Impurity-A (correlation coefficient:1.000) and 4.5ppm to 75.7ppm for Impurity-B (correlation coefficient:0.999). The method was precise and found percentage of relative standard deviation for six replicate sample preparations of Impurity-A and Impurity-B was below 5.0%. The method accuracy was confirmed based on the recovery studies. Based on the method validation study method was sensitive and selective for quantification both genotoxic impurities.

Soliqua (Lixi Lan): Sustained Long Term Cost Efficacy and Safety When Used in Combination with Metformin and Glimepiride

Background: Previous studies using basal insulin documented the lowest daily dose and least hypoglycemic events when combined with Glimepiride and Metformin while attaining desirable glycemic control. However, Pivotal trials with Soliqua excluded Glimepiride as a part of therapy as well as subjects with moderate obesity (BMI &gt; 35kg/m2). Moreover, these trials were relatively short term.&#x0D; Objective: Assess long term efficacy and safety of Soliqua in combination with Glimepiride and Metformin in subjects with type 2 diabetes irrespective of BMI in ‘real world’ experience.&#x0D; Subjects: 30 adults with type 2 diabetes, age range 32-72 years with HbA1C &gt;7.5% while receiving therapy with 1) Glimepiride, Metformin and Basal insulin and 2) Metformin and/or DPP 4 inhibitors and/or other SUs and /or GLP1 RA and/or Basal insulin and/or prandial insulin. Type 2 diabetes was confirmed by presence of C-peptide. Subjects with history of gastroparesis, Triglycerides over 300 mg/dl and pancreatitis were excluded. Subjects with elevated liver enzymes, over 2.5 times normal and EGFR &lt; 30 ml/min were excluded as well.&#x0D; Methods: All prior therapies were discontinued. All subjects were started on Glimepiride 8 mg, Metformin 1000-2000 mg and SC Soliqua was initiated prior to breakfast with daily dose 15 or 30 units as recommended. Daily dose was increased by 2 units every 3 days until AM fasting plasma glucose of 80-130 mg/dl was attained or the dose of 60 units was reached. The stable daily dose of Soliqua was continued until the time of analysis. Comparisons were conducted between body weights (kg), fasting plasma glucose (FPG) and HbA1C prior to initiation of combination therapy (pre Rx) and every 3-6 months until the time of analysis (post Rx).&#x0D; Results: BMI ranged between 22-67 kg/m2. Duration of diabetes was 5-25 years. Duration of therapy with the combination therapy range, 7-56 months. Subjects were divided into 2 groups according to desirable HbA1C levels as per recommendations by ADA: 1) desirable HbA1C is &lt; 7.0%, 2) desirable HbA1C 7-8 %. Both Fasting plasma glucose (mg/dl) and HbA1C (%) declined from 167 ± 10 and 9.7 ± 0.8 to 114 ± 4 and 7.6± 0.3 at the time of analyses (post Rx) respectively in the whole cohort. In 4 (0.13 %) morbidly obese subjects, FPG and HbA1C levels declined though not achieving desirable glycemic goals despite receiving maximal daily dose, 60 units of Soliqua. All four belonged to group 1. In the remaining 17 subjects desirable glycemic levels were attained and maintained. In group 2, desirable glycemia was reached in all 9 subjects. Symptomatic hypoglycemic events confirmed by blood sugar &lt;70 mg/dl were reported by 4 subjects, none requiring secondary assistance. No severe hypoglycemia was reported. Mean daily dose of Soliqua was lower when compared to the pivotal trials.&#x0D; Conclusion: Soliqua is effective and safe in the long term in all subjects irrespective of BMI when administered in combination with Glimepiride and Metformin. Moreover, lesser daily dose required to attain desirable glycemia with this oral combination may render it to be effective without attaining maximum daily dose in subjects with higher BMIs documented in pivotal trials using Metformin alone.

Effects of Recovery-Orientation on the Use of Forced Medication and Maximum Daily Drug Dose: The "Weddinger Modell".

Objective: The aim of the present study was to analyze the effects of the implementation of the Recovery-orientated psychiatric care concept “Weddinger Modell” on the incidence of forced medication, the total number of forced medication incidents per affected case, the maximum dose of a singular forced medication and the maximum voluntary daily drug dose of different psychotropic drugs administered during an inpatient stay.Methods: This retrospective case-control study included 234 patients. A pre/post-comparison of patients on two acute psychiatric wards before (control group, n = 112) and after (intervention group, n = 122) the implementation of the Weddinger Modell in 2010 was performed. Patient data was selected at two reporting periods before and at two reporting periods after 2010.Results: No significant differences were found in the incidence of forced medication and the total number of forced medications. A significant reduction of the maximum forced medication dose of haloperidol in the intervention group was seen. Furthermore, the analysis of the intervention group showed a significant reduction of the maximum voluntary daily drug doses of clozapine, haloperidol and risperidone.Discussion: The results indicate that the implementation of the Weddinger Modell had no effect on the incidence of forced medication, but it can help to improve the approach to psychotropic drugs. Despite the reduction of mechanical coercive measures by the model, as shown in a previous study, there is no increase in forced medications or administered drug doses. Focus on Recovery helps in reducing coercion in acute psychiatric care.

Knowledge and Attitudes towards Acetaminophen Use in Saudi Arabia

<p style="text-align: justify;"><strong>Background:</strong> Despite the common use of acetaminophen and its safety profile, cases of acetaminophen-induced hepatic toxicities have been reported due to unintentional duplication that mostly results from the public significant lack of knowledge. This research aims to assess the public awareness towards the safe use of acetaminophen in Saudi Arabia. <strong>Methods:</strong> A cross-sectional study that targeted the adults in Saudi Arabia that was carried out using self-administered questionnaire. The data obtained included sociodemographic characteristics, the pattern of use, the attitude, as well as the knowledge of the general public towards acetaminophen. <strong>Results:</strong> Data presented in this study showed that a significant majority of the respondents (84.11%) used acetaminophen without their physician&rsquo;s prescription as needed, (66%) denied the development of side effects after using acetaminophen. In terms of the participants&rsquo; knowledge and awareness towards the usage of acetaminophen and its safety, a pronounced proportion of the respondents (53.65%) incorrectly identified the maximum daily dose of acetaminophen and only (16.2%) could. A significant minority of the participants (27%) admitted relying on their own knowledge as the primary source of information. Among the participants (54.69%) denied receiving education on acetaminophen from health care professionals. A marked distinction was observed between the respondents with higher educational level as well as younger individuals regarding the identification of the maximum daily dose (p = 0.0034) and (p = 0.039), respectively.<strong> Conclusion:</strong> There is a concerning inadequacy of the public awareness about the appropriate use of acetaminophen. <p style="text-align: justify;"><strong>Key words:</strong> Acetaminophen, Knowledge, Non-prescription medications, Over dosage, Paracetamol.

Methadone Switching for Cancer Pain: A New Classification of Initiation Protocols, Based on a Critical Literature Review

Background: The initiation of methadone, a known effective analgesic for cancer pain, is complex. The existing protocols are often inadequately described; therefore, a classification of literature is needed. We reviewed and classified the recent literature on methadone initiation protocols in cancer patients experiencing severe pain. Objective: To provide a new classification of initiation protocols, based on a critical literature review. Data Sources: The MEDLINE database was searched for articles published until March 25, 2021, using the terms "cancer pain," "methadone," "methadone introduction," or "methadone initiation." The search was limited to human studies, randomized controlled trials (RCTs), other clinical trials, meta-analyses, and case reports. Selected articles were assessed for initiation details (rapid or progressive), administered dose (fixed rescue dose or ad libitum), and dose calculation (fixed or progressive ratios using morphine equivalent daily dose [MEDD] for daily or unitary dose). Results: Twenty-four publications that met our inclusion criteria were analyzed. No large-scale prospective double-blind RCTs with robust design were identified. Most studies assessed relatively small numbers of patients. Eight initiation types were identified, of which three involved seven "high quality" studies: "rapid switch-fixed doses and rescue dose-progressive daily ratio," "progressive switch-fixed dose and rescue dose-progressive daily ratio," and "rapid switch-ad libitum-fixed ratio for unitary dose" protocols. This classification provides the latest information on methadone initiation protocols. The total daily dose of methadone varied largely across protocols. Conclusion: We recommend a maximal daily methadone dose of 100 mg (3 doses of 30 mg or 5 doses of 20 mg) for MEDD <500 mg, when the two "ad libitum" protocols are used. Further clinical research on this topic is warranted.

Effect of comprehensive, individualized, person‐centered management (CI‐PCM) on psychotropic medication usage in advanced Alzheimer’s persons in a 28‐week randomized controlled trial

AbstractBackgroundBehavioral and Psychological Symptoms of Dementia (BPSD) are burdensome and disturbing for caregivers and persons living with Alzheimer’s disease (AD). They are also a primary cause of institutionalization of Alzheimer’s persons. Physicians use psychotropic medications to treat the BPSD of AD. Many of these medications have deleterious consequences as evidenced in part by their black box warnings. We published results of a 28‐week, clinician‐blind, randomized, controlled trial of our CI‐PCM program in moderate‐to‐severe, community‐residing, Alzheimer’s persons receiving memantine (Reisberg…Kenowsky, Dement Geriatr Cogn Disord, 2017). The BPSD were examined using the Behavioral Pathology in Alzheimer’s Disease‐Frequency Weighted severity scale, which showed significant benefit in the CI‐PCM subject group at week 28 (p&lt;0.05).MethodsWe examined the magnitude of usage of psychotropic medications used to treat BSPD in subjects from our 2017 study who were randomized to receive Usual Community Care (UCC) or the CI‐PCM Program. Psychotropic medications used to treat other conditions were excluded. Subjects were evaluated at baseline and weeks 4, 12 and 28. We examined the ratio of daily psychotropic medication usage in the two groups. Psychotropic medications were compared by examining the percent of the maximum daily dosage of each medication taken cumulatively throughout each study observation period from week 4 to week 28. The Wilcoxon rank sum test was used to analyze the difference between the two groups.ResultsAt baseline, the group randomized to UCC consumed significantly more psychotropic medication than subjects randomized to the CIPCM program (p&lt;0.05). Because there was a significant difference between groups at baseline, we analyzed usage in comparison with baseline (see figure 1). The UCC subjects used more psychotropic medication on a per day average relative to baseline from week 4 to week 28 than the CI‐PCM subjects (p&lt;0.01). The total amount of psychotropic medication taken, in comparison with baseline, was significantly lower in CI‐PCM subjects from weeks 4 to 28 (p&lt;0.0001).ConclusionsCI‐PCM subjects took significantly less psychotropic medication and their BPSD symptomatology significantly improved. The CI‐PCM program is a safe, highly efficacious nonpharmacologic intervention that significantly reduces both BPSD symptomatology and psychotropic medication usage in advanced AD persons.