Study on the chemical stability of β-lactam antibiotics in concomitant simple suspensions with magnesium oxide

Kato G., Mitome H., Miyauchi Y., Takeda S., Toyota Y., Hidaka N., Tanaka M., Akira K.

Abstract Background Difficulty in taking solid medicines is a common issue particularly for the elderly because of a decline in swallowing function, also known as dysphagia. For patients with such a dysfunction, a simple suspension method, in which solid medicines are disintegrated and suspended using warm water, has been developed and widely used in Japanese clinical settings. However, there is little information on drug stability in the simple co-suspension of multiple formulations especially including acidic or alkaline ones. In this study, the chemical stability of typical cholesterol-lowering drugs was investigated in a simple co-suspension with alkaline magnesium oxide (MgO) which is frequently used as a laxative or antacid in Japan. Methods A cholesterol-lowering drug (one tablet) was soaked with or without MgO in warm water (55°C), and the vessel was left at room temperature for 10 min or 5 h. The suspensions prepared were then analyzed by high-performance liquid chromatography. Degradation products were analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry for the structural elucidation. Results In the simple co-suspension with MgO, no significant degradation was observed for atorvastatin or pravastatin, while a significant decrease of the recovery from the co-suspension was observed for rosuvastatin after 5 h. On the other hand, simvastatin and ezetimibe co-suspended with MgO were partially degraded to simvastatin acid and a pyran compound, respectively. Conclusions A simple co-suspension with MgO is feasible for atorvastatin, pravastatin, and rosuvastatin, although the rosuvastatin tablet should not be left soaking for a long time. Further it is inadvisable to suspend simvastatin or ezetimibe together with MgO because of their partial degradation.

Kim D., Kim S., Kwon Y., Kim Y., Park H., Kwak K., Lee H., Lee J.H., Jang K., Kim D., Lee S.H., Kang L.

Crul M., Breukels O., Ng S., Le Feber M., Kuijpers E., Smeets O.

Some drugs need processing before they can be administered or dispensed.We measured airborne exposure of pharmacy staff to small particles when performing these tasks.Reconstitution of powdered drugs in vials; crushing, splitting, and counting of tablets; and opening of capsules, using different ventilation strategies, were investigated in 5 pharmacies following a worst case approach. Airborne particulate matter was determined for a range of particles sizes.Mean particle concentrations ranged from not-detectable to 1.03 μg/m3 (< 1 micrometer) and 589.7 μg/m3 (< 10 micrometer). Dust exhaust made tasks safer. Most hazardous was pouring out tablets from a bulk supply, and least hazardous was reconstitution of a powder for injection.Occupational exposure during routine handling of drugs can occur, but the risks vary greatly with the nature and duration of the tasks.

Kato G., Mitome H., Teshima K., Tawa K., Hakuba Y., Tanabe T., Funahashi T., Hatae N., Koike Y., Hasebe M., Hidaka N., Tanaka M., Akira K.

Abstract The exposure of healthcare workers to antineoplastic drugs in hospitals has been recognized to be harmful. To minimize the risk of exposure, the removal of these drugs from work environments, such as compounding facilities, has been recommended. In our previous paper, the degradation and inactivation efficacy of ozone water, which is being introduced into Japanese hospitals as a chemical decontamination agent, was reported for its effects on typical antineoplastic drugs (gemcitabine, irinotecan, paclitaxel). This article aims to further investigate the efficacy of ozone water for eight antineoplastic drugs to clarify its application limitations. A small amount (medicinal ingredient: typically ca. 1.5 μmol) of formulation containing 5-fluorouracil, pemetrexed, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, doxorubicin, or docetaxel was mixed with 50 mL of ozone water (~8 mg/L), and the resulting solutions were analyzed by high-performance liquid chromatography over time to observe the degradation. Consequently, the ozonation was overall effective for the degradation of the drugs, however this varied depending on the chemical structures of the drugs and additives in their formulations. In addition, after the parent drugs were completely degraded by the ozonation, the degradation mixtures were subjected to 1H nuclear magnetic resonance spectroscopy and evaluated for mutagenicity against Salmonella typhimurium strains and cytotoxicity against human cancer cells. The degradation mixtures of cisplatin and ifosfamide were mutagenic while those of the other drugs were non-mutagenic. Further, the ozonation resulted in clear decreases of cytotoxicity for 5-fluorouracil, oxaliplatin, and doxorubicin, but increases of cytotoxicity for pemetrexed, cisplatin, cyclophosphamide, and ifosfamide. These results suggest that the ozone water should be restrictedly used according to the situation of contamination in clinical settings because the ozonation enhances toxicity depending on the drug even if degradation is achieved.

Murahashi T., Arai M., Ogata K., Matsumoto M., Higuchi T.

Turner J., Muraoka A., Bedenbaugh M., Childress B., Pernot L., Wiencek M., Peterson Y.K.

Beta-lactam antibiotics remain one of the most commonly prescribed drug classes, but they are limited by their propensity to cause hypersensitivity reactions (e.g., from allergy to anaphylaxis) as well as by the emergence of bacteria with a myriad of resistance mechanisms such as β-lactamases. While development efforts continue to focus on overcoming resistance, there are ongoing concerns regarding cross-contamination of β-lactams during manufacturing and compounding of these drugs. Additionally, there is a need to reduce levels of drugs such as β-lactam antibiotics in waste-water to mitigate the risk of environmental exposure. To help address future development of effective remediation chemistries and processes, it is desired to better understand the structural relationship among the most common β-lactams. This study includes the creation of a class-wide structural ordering of the entire β-lactam series, including both United States Food and Drug Association (US-FDA)-approved drugs and experimental therapies. The result is a structural relational map: the “Lactamome,” which positions each substance according to architecture and chemical end-group. We utilized a novel method to compare the structural relationships of β-lactam antibiotics among the radial cladogram and describe the positioning with respect to efficacy, resistance to hydrolysis, reported hypersensitivity, and Woodward height. The resulting classification scheme may help with the development of broad-spectrum treatments that reduce the risk of occupational exposure and negative environmental impacts, assist practitioners with avoiding adverse patient reactions, and help direct future drug research.

Brauning A., Rae M., Zhu G., Fulton E., Admasu T.D., Stolzing A., Sharma A.

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging (“inflammaging”). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.

Kang S.J., Cho Y.S., Lee T.H., Kim S., Ryu H.S., Kim J., Park S., Lee Y.J., Shin J.E.

Seung Joo Kang, Young Sin Cho, Tae Hee Lee, Seong-Eun Kim, Han Seung Ryu, Jung-Wook Kim, Seon-Young Park, Yoo Jin Lee, and Jeong Eun Shin; Constipation Research Group of the Korean Society of Neurogastroenterology and Motility. J Neurogastroenterol Motil 2021;27:495-512. https://doi.org/10.5056/jnm20210

Takano Y., Kabe H., Mizoi K., Hakoda K., Mineno T., Yano K., Ogihara T.

In the simple suspension method, the intended medicine is suspended in hot water when administered to a patient by tube. Suspension of the laxative, magnesium oxide is reported to hydrolyze ester-type drugs. Because several angiotensin converting enzyme (ACE) inhibitors have ester bonds in their structure, magnesium oxide may cause incompatibility when suspended with an ACE inhibitor. The purpose of this study was to clarify the effect of magnesium oxide on the stability of eight kinds of ACE inhibitors in the simple suspension method.

Kunieda K., Kurata N., Yoshimatsu Y., Ohno T., Shigematsu T., Fujishima I.

The simple suspension method (SSM), developed by Kurata in 1997, is a way to suspend tablets and capsules in warm water for decay and suspension prior to their administration. This method is safe and has various advantages such as the avoidance of tube clogging and the loss of the drug. This study aimed to investigate whether a higher percentage of commonly used drugs could pass through nutrition tubes effectively using SSM, relative to that using the conventional crushing method. A tablet or capsule was inserted into a 20 mL syringe with warm water (at 55 °C). After 10 min, it was shaken in the syringe. The suspension liquid was injected into tubes of the following sizes: 8 Fr, 10 Fr, 12 Fr, 14 Fr, 16 Fr, and 18 Fr. A total of 3686 tablets and 432 capsules that are frequently used in Japan were tested. Using SSM, 3377 (91.6%) tablets and 359 (83.1%) capsules disintegrated within 10 min and passed through the tube without clogging it in the tube passage test. With the conventional crushing method, 2117 tablets (57.4%) and 272 capsules (63.0%) could be crushed. SSM reduced the risk of tube clogging and drug loss with more drugs than that with the conventional crushing method. The number of drugs indicated for administration by SSM is greater than that indicated by the conventional crushing method. Further studies are needed to consider its utility compared to conventional methods for dysphagia patients in clinical settings.

Mori H., Tack J., Suzuki H.

Magnesium oxide has been widely used as a laxative for many years in East Asia, yet its prescription has largely been based on empirical knowledge. In recent years, several new laxatives have been developed, which has led to a resurgence in interest and increased scientific evidence surrounding the use of magnesium oxide, which is convenient to administer, of low cost, and safe. Despite these advantages, emerging clinical evidence indicates that the use of magnesium oxide should take account of the most appropriate dose, the serum concentration, drug–drug interactions, and the potential for side effects, especially in the elderly and in patients with renal impairment. The aim of this review is to evaluate the evidence base for the clinical use of magnesium oxide for treating constipation and provide a pragmatic guide to its advantages and disadvantages.

Christmas C., Rogus‐Pulia N.

Swallowing problems, or dysphagia, are common as people age, and are associated with significant negative outcomes, including weight loss, pneumonia, dehydration, shortened life expectancy, reduced quality of life, and increased caregiver burden. In this article, we will discuss the complex process of swallowing in normal circumstances and with healthy aging, then review etiologies that contribute to dysphagia. We will discuss approaches to evaluating and treating dysphagia, providing relevant data where they are available. We highlight the desperate need for high-quality research to guide best practices in treating dysphagia in older adults. J Am Geriatr Soc 67:2643-2649, 2019.

Mori H., Suzuki H., Hirai Y., Okuzawa A., Kayashima A., Kubosawa Y., Kinoshita S., Fujimoto A., Nakazato Y., Nishizawa T., Kikuchi M.

Although magnesium oxide is widely used as a laxative, alterations in serum magnesium concentrations among patients taking daily magnesium oxide have not been clarified. The present retrospective, cross-sectional study investigated the risk factors for hypermagnesemia in patients taking daily oral magnesium oxide. Of 2,176 patients administered daily magnesium oxide, 193 (8.9%) underwent assays of serum magnesium concentrations and were evaluated. High serum magnesium concentration and hypermagnesemia were defined as serum magnesium concentrations ≥2.5 mg/dl and ≥3.0 mg/dl, respectively. Of the 193 patients taking daily magnesium oxide, 32 (16.6%) had high serum magnesium concentration and 10 (5.2%) had hypermagnesemia. Factors associated with hypermagnesemia included chronic kidney disease (CKD) grade 4 (p = 0.014) and magnesium oxide dosage (p = 0.009). Factors associated with high serum magnesium concentration included magnesium oxide dosage >1,000 mg/day (p = 0.004), CKD grades 4 (p = 0.000) and concomitant use of stimulant laxatives (p = 0.035). Age, however, was not associated with hypermagnesemia or high serum magnesium concentration. In conclusion, renal function and magnesium oxide dosage, but not age, were associated with hypermagnesemia and high serum magnesium concentration in patients with functional constipation taking daily magnesium oxide.

Wakai E., Ikemura K., Sugimoto H., Iwamoto T., Okuda M.

Magnesium oxide (MgO), an antacid and laxative, is widely used in Japan to treat constipation and peptic ulcers. Because serum Magnesium (Mg) levels are elevated in elderly and/or patients with renal failure, its periodic monitoring is recommended for patients prescribed MgO, in order to prevent MgO-induced hypermagnesemia. However, there is little information regarding the factors contributing to the development of MgO-induced hypermagnesemia. In the present study, we retrospectively investigated the risk factors of hypermagnesemia in patients prescribed MgO. Data of 3258 patients hospitalized in Mie University Hospital between October 2015 and September 2017, who were prescribed MgO tablets, were extracted from the electronic medical records. According to the inclusion and exclusion criteria, 320 of the 3258 patients were enrolled in this study. Hypermagnesemia was defined as serum Mg levels ≥2.5 mg/dL (by the Common Terminology Criteria for Adverse Events version 4.0). Uni- and multivariate analyses were performed to identify risk factors for the development of hypermagnesemia in patients prescribed MgO using the following variables: age, estimated glomerular filtration rate, blood urea nitrogen levels, MgO dose, duration of MgO administration, and co-administrated proton pump inhibitors, H2 blocker (famotidine), vitamin D3 drugs, and diuretics. Seventy-five patients out of 320 (23%) developed grade 1 and grade 3 hypermagnesemia, with the occurrence of grade 1 and grade 3 in 62 (19%) and 13 (4%) patients, respectively. Multivariate logistic regression analyses indicated 4 independent risk factors for hypermagnesemia comprising estimated glomerular filtration rate ≤ 55.4 mL/min (odds ratio (OR): 3.105, P = 0.001), blood urea nitrogen ≥22.4 mg/dL (OR: 3.490, P < 0.001), MgO dose ≥1650 mg/day (OR: 1.914, P = 0.039), and duration of MgO administration ≥36 days (OR: 2.198, P = 0.012). The occurrence rate of hypermagnesemia was elevated in accordance with these risk factors. These results suggest that a periodic monitoring of serum Mg levels is strongly recommended in MgO prescribed patients, especially in those with multiple risk factors for hypermagnesemia. The present findings provide useful information for the safe management of MgO therapy.

Sestili M., Logrippo S., Cespi M., Bonacucina G., Ferrara L., Busco S., Grappasonni I., Palmieri G., Ganzetti R., Blasi P.

Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first to focus on how hospitalization affected the rate of potentially inappropriate prescriptions (PIPs) and the incidence of dosage form-related PIPs in elderly patients with dysphagia. Data was collected by reviewing patient medical records in the Italian National Research Center on Aging of Ancona. The therapy at admission and discharge was analysed in terms of: inappropriate drug associations, inappropriate drugs for dysphagic patients, inappropriate dosage forms and inappropriate dosage form modifications. Forty-one dysphagic patients with an average age of 88.3 years were included in the study and 451 prescriptions were analysed. PIPs were widespread at admission, and hospitalization did not improve the situation in a statistically significant manner. The most common PIPs identified (>80%) were related to dosage form selection and modification. This study highlights a clear need for continuing medical education about prescription appropriateness and modification of solid dosage forms in patients with dysphagia.