Strategies for appetite suppression: A key player in the management of diabetes and obesity.

People with diabetes and/ or obesity are advised to curtail their calorie intake in order to improve their glycaemic control and reduce their weight. However, many patients complain of an inability to manage their appetite and thereby find it difficult to control their calorie intake. Dysregulated appetite leads to glycaemic swings, and creates a challenge for metabolic management. Moreover, short term non-structured methods to suppress appetite often can cause a rebound excess of food intake, which can even overshoot more than the baseline intake. This article shares the non-pharmacological heuristics and hacks to help suppress and optimize appetite which can be used in day-to-day clinical practice.

The Ominous Octet of Obesity: A framework for obesity pathophysiology.

The pathogenesis of obesity is complex and is beyond the simple equation of excess calorie intake and inadequate calorie expenditure. It involves the role of multiple organ systems and these complex interactions are often challenging to address in a busy clinical practice. We propose a simplified framework akin to the ominous octet of diabetes, to help understand the role of these different organ systems in relation to obesity. The Ominous Octet of obesity includes the hypothalamus, islet cells of Langerhans, gastrointestinal tract, adipose tissue, adrenal gland, gonads, thyroid gland and the muscle. This framework would also help to understand the use of different therapeutic targets in patients with obesity and improve the care of these patients.

The Triple Combination Phentermine Plus 5-HTP/Carbidopa Leads to Greater Weight Loss, With Fewer Psychomotor Side Effects Than Each Drug Alone.

Obesity has become a serious public health problem. Although diet, surgery, and exercise are the primary treatments for obesity, these activities are often supplemented using appetite suppressants. A previous study reported that obesity specialists frequently prescribed a new drug combination for its treatment that includes phentermine (Phen; dopaminergic appetite suppressant), a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP; an appetite suppressant that increases the 5-HT concentration), and carbidopa (CB; peripheral blocker of conversion of 5-HTP to 5-HT). Despite its widespread use, there is neither a preclinical study confirming the drug efficacy nor studies of its effects on the brain. To fill this gap, in rats for seven consecutive days, we administered Phen intraperitoneally at different doses either alone or in combination with a fixed dose of 5-HTP/CB. In a different group, we infused drugs via an intraperitoneal catheter while extracellular-recordings were performed in the nucleus accumbens shell (NAcSh), a brain region with dopamine-releasing effects that is involved in the action of appetite suppressants. We found that the triple-drug combination leads to greater weight-loss than each drug alone. Moreover, and as the treatment progresses, the triple drug combination partially reversed psychomotor side-effects induced by Phen. Electrophysiological results revealed that Phen alone evoked a net inhibitory imbalance in NAcSh population activity that correlated with the onset of psychomotor effects. In addition, and unlike the greater weight loss, the addition of 5-HTP/CB did not alter the Phen-evoked inhibitory imbalance in NAcSh responses. Subsequent experiments shed light on the underlying mechanism. That is the majority of NAcSh neurons modulated by 5-HTP/CB were suppressed by Phen. Notably, and despite acting via a different mechanism of action (DA for Phen vs. 5-HT for 5-HTP/CB), both drugs recruited largely overlapping NAcSh neuronal ensembles. These data suggest that the neural correlates of the greater weight loss could be located outside the NAcSh, in other brain circuits. Furthermore, we conclude that Phen + 5-HTP/CB is a potential treatment for overweight and obesity.

Acute Pancreatitis Secondary to Use of Appetite Suppressant: Garcinia cambogia.

Due to the global epidemic of obesity, weight loss and appetite suppressant herbal products are quite popular. As these medications are not United States Food and Drug Administration-approved and are regulated as dietary supplements, little evidence exists regarding their safety. This case discusses an 82-year-old man with the past medical history of obesity who presented to the emergency department with abdominal pain in the epigastric region. His serum lipase was elevated, and an abdominal computed tomography revealed acute pancreatitis (AP). He reported two episodes of AP in the past. He denied any alcohol use and reported no recent changes in his medications. He reported taking Garcinia cambogia (GC) recently as an appetite suppressant. Due to prior cholecystectomy, no alcohol abuse, no recent changes in medications and recent use of GC, a likely etiology of AP was thought to be secondary to the use of GC. He was treated with bowel rest and intravenous fluid hydration with significant improvement in his symptoms. He was advised to avoid GC in the future. Clinicians should be vigilant in evaluating their patients with AP and should get a meticulous history regarding their use of over-the-counter medications and herbal products.

Consumo de formulações emagrecedoras e risco de transtornos alimentares em universitários de cursos de saúde / Consumption of dietary substances and their association with risk of eating disorders in college students

RESUMO Objetivo Avaliar o consumo de formulações emagrecedoras e sua possível associação com o risco de transtornos alimentares (TAs) em universitários de cursos de saúde de diversos níveis socioeconômicos. Métodos Estudo epidemiológico transversal, realizado com 276 universitários matriculados em quatro cursos da área da saúde. Para a obtenção dos dados, utilizaram-se três instrumentos autoaplicáveis: o Eating Attitudes Test (EAT-26), o Bulimic Investigatory Test of Edinburgh (BITE) e, para investigar o consumo de formulações emagrecedoras, um questionário elaborado pela própria equipe de pesquisa. Para análise dos dados, aplicou-se o teste qui-quadrado, adotando-se o nível de significância de 5%. Resultados Vinte e um universitários apresentaram risco de TA pela escala EAT-26, correspondente a 7,6% dos pesquisados. A frequência do uso de formulações emagrecedoras foi de 7,2%. Houve associação significativa (p < 0,001) entre o uso de formulações emagrecedoras e a presença de risco para TA (33,3%), com percentual muito elevado quando comparado ao percentual de entrevistados sem risco de TA que estavam em uso de medicamentos (5,1%). Conclusões O consumo de formulações emagrecedoras esteve associado tanto à presença de risco para TA, nas escalas EAT-26 e BITE, quanto aos níveis socioeconômicos, principalmente para a classe de renda C.

ABSTRACT Objective to evaluate the consumption of weight loss formulations and their possible association with risk of eating disorders (ED) in university students of health courses of different socioeconomic levels. Methods A cross-sectional epidemiological study was carried out with 276 university students enrolled in four health courses. To obtain the data, three self-applied instruments were used: the Eating Attitudes Test (EAT-26), the Bulimic Investigatory Test of Edinburgh (BITE) and to investigate the consumption of weight-loss formulations a questionnaire prepared by the research team was used. For the data analysis, the chi-square test was applied, adopting the level of significance of 5%. Results Twenty-one university students presented a risk of ED by the EAT-26 scale, corresponding to 7.6% of the respondents. The frequency of use of weight loss formulations was 7.2%. There was a significant association (p < 0.001) between the use of weight loss formulations and the presence of risk for ED (33.3%), with a very high percentage when compared to the percentage of non-ED respondents who were using medication (5.1%). Conclusions The consumption of dietary formulations was associated with both the presence of risk for ED, on the EAT-26 and BITE scales, and on socioeconomic levels, especially for income class C.

Preparation of Pinolenic Acid Concentrates from Pine Nut Oil Fatty Acids by Solvent Fractionation.

Pinolenic acid (PLA), which is a fatty acid (FA) exclusively found in the oils of edible pine nuts, has an appetite-suppression effect, thereby being effective to reduce body weight in humans. PLA concentrates would be suitable for use in functional foods and nutraceuticals due to the health benefits of PLA. PLA concentrates were prepared from free FA (FFA) obtained from pine nut oil using solvent fractionation. Siberian pine nut oil containing 18.3 wt% PLA was used as the starting material for the fractionation. The fractionation was performed in n-hexane at ultra-low temperatures down to -85°C. The PLA concentrates produced under the optimal conditions established in this study (temperature, -85°C; n-hexane-to-FFA ratio (v/w), 30:1; fractionation time, 36 h) contained 69.8 wt% PLA. The yield of PLA was 77.4 wt% of the initial PLA weight in the FFA. These results suggest that solvent fractionation is a more effective approach to prepare PLA concentrates with higher PLA contents at a particular yield of PLA than published methods using urea crystallization (e.g., PLA content = ~47 wt%, yield of PLA = ~77 wt%, Woo et al. (2016)) or lipase-catalyzed reactions (e.g., PLA content = ~30 wt%, yield of PLA = ~61 wt%, Lee et al. (2011)). The resulting PLA concentrates contained 11 of the 12 different species of FA present in the FFA, thereby indicating that the PLA concentrates prepared by solvent fractionation have more diverse FA profiles than those prepared by urea crystallization (e.g., 7 species of FA, Woo et al. (2016)).

Enzymatic Synthesis of Structured Monogalactosyldiacylglycerols Enriched in Pinolenic Acid.

We enzymatically prepared structured monogalactosydiacylglycerols (MGDGs) enriched in pinolenic acid (PLA). PLA-enriched free fatty acids (FFAs) containing ∼86 mol % PLA were produced from an FFA fraction obtained from pine nut oil (PLA content, ∼13 mol %) by urea crystallization. Commercial MGDGs (5 mg) were acidolyzed with PLA-enriched FFAs using four commercial immobilized lipases as biocatalysts. The reaction was performed in acetone (4 mL) in a stirred-batch reactor. Lipozyme RM IM (immobilized Rhizomucor miehei lipase) was the most effective biocatalyst for the reaction. Structured MGDGs containing 42.1 mol % PLA were obtained under optimal reaction conditions: temperature, 25 °C; substrate molar ratio, 1:30 (MGDGs/PLA-enriched FFAs); enzyme loading, 20 wt % of total substrates; and reaction time, 36 h. The structured MGDGs were separated from the reaction products at a purity of 96.6 wt % using silica column chromatography. The structured MGDGs could be possibly used as emulsifiers with appetite-suppression effects.

Stimulants for the Control of Hedonic Appetite.

The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug.

Clinical and echographic characteristics of patients exposed to fenfluramin or its derivatives: Results of a prospective, single-centre, observational study.

BACKGROUND: Fenfluramine and its derivatives have been associated with significant risk of developing valvular heart disease but its exact prevalence and severity are still debated. AIM: To evaluate the clinical and echocardiographic characteristics of patients hospitalized in a cardiology centre and who had past exposure to these drugs. METHODS: Between July 2011 and February 2012, patients admitted to the hospitalization and intensive care units at the University Centre of Montpellier, France were questioned about past exposure to fenfluramine or its derivatives. In patients who reported exposure, a questionnaire assessing prescribing patterns and medical history was proposed and echocardiography performed. All of the usual echocardiographic variables were analysed. We applied criteria from a French multicentre registry for diagnosis of drug-induced valvulopathy: leaflets and subvalvular apparatus thickening and retraction, leaflets loss of coaptation, no calcification, and no stenosis. RESULTS: Ninety-five patients exposed to these drugs were included. The majority were female (n=62, 65.3%), 53.2% (n=50) had diabetes and 90.5% (n=86) were exposed to benfluorex. Mean treatment duration was 52.3months (95% confidence interval [CI] 39.0-65.6). Valvular regurgitations were observed in 64.0% of patients (n=57) while 19.8% (n=17) had pulmonary hypertension. Highly probable fenfluramine-induced regurgitations were present in 18.6% (n=16) of patients, possibly fenfluramine-induced regurgitations in 38.2% (n=34) of patients, and unlikely fenfluramine-induced regurgitations in 25.8% (n=23) of patients. Highly probable fenfluramine-induced regurgitations were mild to moderate in severity in all except three patients. CONCLUSION: Considering the frequency of probable or possible fenfluramine-induced regurgitations and in the absence of definite knowledge about the evolution of drug-induced valvular disease, systematic questioning about fenfluramine use may be advisable in hospitalized cardiac patients.

Há irracionalidades no consumo de inibidores de apetite no Brasil? Uma análise farmacoeconométrica de dados em painel / Are there irrationalities in the consumption of anti-obesity drugsin Brazil? A pharmaco-econometric analysis of panel datasets

Este estudo busca analisar os determinantes do consumo de inibidores de apetite (anfepramona, femproporex, mazindol e sibutramina) por meio da estimação de um modelo dinâmico de dados em painel para as capitais brasileiras e do Distrito Federal (DF) no período de 2009 a 2011. Os resultados revelam que o consumo de inibidores de apetite não acompanhou a distribuição geográfica dos indivíduos com excesso de peso e com obesidade nas unidades estudadas. Do consumo recorrente de inibidores, 79% são explicados pelo ocorrido no passado. Dentre as variáveis que explicam o consumo de inibidores, destacam-se os percentuais de adultos com obesidade e que dos que consomem frutas e hortaliças e a taxa de cobertura de planos de saúde. A análise farmacoeconométrica sugere que há problemas no uso racional dos inibidores de apetite nas capitais brasileiras e no DF, seja no que tange ao consumo desses medicamentos com outros fármacos - considerados ilegais pelo Conselho Federal de Medicina e pela Anvisa - e, também, na indicação terapêutica de uso desses produtos.

The scope of this study is to analyze the determinants of the use of appetite suppressants (amfepramone, femproporex, mazindol and sibutramine) through the estimation of a dynamic panel dataset model for the Brazilian state capitals and the Federal District (DF) in the period from 2009 to 2011. The results show that consumption of appetite suppressants did not follow the geographic distribution of overweight and obese individuals across the capitals and DF. There is a recurrent consumption of appetite inhibitors, in which 79% of the current consumption of these drugs is explained by past consumption. Among the variables that explain the use of inhibitors, the percentage of obese adults, the percentage of adults who habitually consume fruit and vegetables, and the coverage rate of health plans stand out. The pharmaco-econometric analysis suggests that there are problems in the rational use of appetite suppressants in the Brazilian state capitals and the Federal District with respect to both the combined consumption of these drugs with other medicines - deemed illegal by the Federal Council of Medicine and ANVISA - and in the therapeutic prescription of these products.

Uso de moderadores de apetite entre estudantes da área da saúde na Região Sul do Brasil / The use of appetite suppressants among health sciences undergraduate students in Southern Brazil

OBJETIVO: Estabelecer a prevalência do uso de moderadores de apetite entre estudantes da área da saúde na Região Sul do Brasil. MÉTODOS: Estudantes universitários (n=300) de sete cursos da área da saúde da Universidade de Caxias do Sul completaram um questionário sobre o uso de moderadores de apetite. RESULTADOS: Uma significativa porcentagem da amostra (15%; n=45) usou moderadores de apetite pelo menos uma vez na vida. As substâncias mais comumente usadas foram drogas estimulantes (5%), incluindo amfepramona (3,3%) e fenproporex (1,7%). O uso de moderadores de apetite foi mais prevalente entre estudantes de Enfermagem (26,7%) e Nutrição (24,4%%). Não foi relatado o uso de moderadores de apetite entre estudantes de Medicina. O uso de anorexígenos foi significativamente mais prevalente entre mulheres. A maioria dos que usaram supressores de apetite o fez sob orientação médica, como também usou tais substâncias por mais de 3 meses. CONCLUSÃO: O uso durante a vida de moderadores de apetite foi significativo entre estudantes da área da saúde, especialmente entre os matriculados em Enfermagem e Nutrição. As drogas estimulantes simpatomiméticas foram os agentes mais comumente usados.

OBJECTIVE: To investigate the prevalence of appetite suppressant use among health sciences students in Southern Brazil. METHODS: Undergraduate students (n=300) from seven health science undergraduate courses of the Universidade de Caxias do Sul completed a questionnaire about the use of substances to suppress appetite. RESULTS: A significant percentage (15%; n=45) of research participants used appetite suppressants at least once in their lives. The most commonly used substances were sympathomimetic stimulant drugs (5%), including amfepramone (3.3%) and fenproporex (1.7%). The lifetime use of appetite suppressants was more prevalent among Nursing (26.7%) and Nutrition (24.4%%) students. There was no reported use of appetite suppressants among medical students. The use of appetite suppressants was significantly more prevalent among women. The majority of those who used these substances did so under medical recommendation. Most of users took appetite suppressants for more than 3 months. CONCLUSION: Lifetime use of appetite suppressants was substantial, being sympathomimetic stimulant drugs the most commonly used agents. Students enrolled in Nursing and Nutrition courses presented a significantly higher prevalence of lifetime use of appetite suppressants.

Evidências advindas do consumo de medicamentos moduladores do apetite no Brasil: um estudo farmacoeconométrico / Evidence for the use of appetite suppressant drugs in Brazil: a pharmacoeconometric study

OBJETIVO: Analisar o consumo de moduladores do apetite (CMA) no Brasil em 2009, condicionado às características dos usuários, do sistema de saúde e de outros medicamentos. MÉTODOS: Estudo farmacoeconométrico com dados em corte transversal para analisar as relações entre o CMA (mg/per capita) e as variáveis independentes selecionadas (gênero, raça/cor, faixa etária, escolaridade, renda, cobertura de planos de saúde e consumo de fluoxetina e clordiazepóxido), mediante análise de regressão linear múltipla. Este estudo utilizou-se dessas variáveis em nível de agregação por estados para 2009. As análises foram realizadas no software Gretl. RESULTADOS: Destacamos que São Paulo registrou o maior CMA, com 97,3 mg/per capita, seguido de Goiás, com 94,8 mg/per capita. O menor consumo foi verificado no Ceará (3,8 mg/per capita). Os maiores consumidores de fluoxetina foram o Rio Grande do Sul, com 58,0 mg/per capita, e Goiás, com 51,5 mg/per capita. O Ceará (2,3 mg/per capita) registrou o menor con-sumo. Para o clordiazepóxido, os maiores valores foram verificados em Minas Gerais (7,5 mg/per capita) e Rio de Janeiro (4,8 mg/per capita), enquanto que o Amazonas (0,08 mg/per capita) obteve o menor consumo. Da análise de regressão destacamos: 1) o CMA está relacionado com renda, escolaridade e consumo de fluoxetina; e 2) raça/cor, gênero, idade, cobertura de plano de saúde e consumo de clordiazepóxido, porém revelaram-se não relacionados com CMA. CONCLUSÃO: Essas evidências podem contribuir para o aprimoramento das ações de regulação, vigilância sanitária e de conduta ética, principalmente, no que tange o consumo "casado" de moduladores do apetite com fluoxetina, o qual é vedado pelo Conselho Federal de Medicina, e, também, pela Anvisa.

OBJECTIVE: Analyze the use of appetite suppressants in Brazil in 2009, according to the characteristics of users, healthcare system, and other drugs. METHODS: Pharmaconeconometric study of cross-sectional data to analyze the relationship between the use of appetite suppressants (mg/per capita) and the independent variables selected (gender, race/color, age, schooling, income, health insurance coverage, and use of fluoxetine and chlordiazepoxide) using multiple linear regression analysis. This study used these variables in level of aggregation by states for 2009. The analyses were performed using the Gretl software. RESULTS: We highlight that São Paulo showed the highest use of appetite suppressants with 97.3 mg/per capita, followed by Goiás with 94.8 mg/per capita. The lowest use of appetite suppressants was seen in Ceará (3.8 mg/per capita). The biggest fluoxetine users were in Rio Grande do Sul, with 58.0 mg/per capita, and in Goiás, with 51.5 mg/per capita. Ceará showed the lowest fluoxetine use (2.3 mg/per capita). For chlordiazepoxide, the highest values were seen in Minas Gerais (7.5 mg/per capita) and in Rio de Janeiro (4.8 mg/per capita), while Amazonas (0.08 mg/per capita) showed the lowest use. Based on regression analysis, we can highlight: 1) the use of appetite suppressants is related to income, education, and fluoxetine use; and 2) race/color, gender, age, health insurance coverage, and use of chlordiazepoxide showed no relation to the use of appetite suppressants. CONCLUSION: These evidences may contribute to the improvement of regulatory actions, sanitary surveillance, and ethical conduct, particularly with regard to the concomitant use of appetite suppressants and fluoxetine, which is prohibited by the Federal Council of Medicine (Conselho Federal de Medicina) and also by Anvisa (Agência Nacional de Vigilância Sanitária - National Health Surveillance Agency).

O uso de inibidores de apetite por mulheres: um olhar a partir da perspectiva de gênero / The use of apetite inhibitors by women: an insight based on the gender perspective

O presente estudo teve como objetivo compreender os motivos que levam mulheres adultas a utilizar medicamentos inibidores do apetite e verificar, a partir da ótica de gênero, como se estabelece a relação dessas mulheres com seus próprios corpos. Orientado pelos princípios da pesquisa qualitativa, utilizou como técnicas de construção de dados a entrevista semiestruturada e a observação direta. Participaram como informantes do estudo seis mulheres usuárias de anorexígenos. Os resultados apontaram que as imagens, a publicidade e as redes sociais contribuem significativamente para a criação de padrões de aparência física e de "estilos de vida", cujo modelo preconiza a boa aparência (corpo magro) e a felicidade conjugal. O corpo magro é representado como algo capaz de alterar condições, ou seja, pessoa gorda = pessoa infeliz; e pessoa magra = pessoa feliz. O estudo mostra que é no corpo como lócus que o papel socialmente destinado às mulheres será produzido e reproduzido.

The scope of this study was to understand the motives that lead adult women to use appetite inhibitors and to establish, from a gender perspective, how these women relate to their own bodies. It was structured around the principles of qualitative research, and the methods of data collection were semi-structured interviews and direct observation. The informants were six women who used appetite inhibitors. The results indicated that images, publicity and social networks contribute significantly to the creation of new standards of physical appearance as well as lifestyles, which establish appearance (a slim body) and a happy marriage as the desired model. The slim body is represented as something able to alter the temperament of the individual, in other words a fat person is an unhappy person and a slim person is a happy person. The study shows that it is in the body per se that the social role destined for women is produced and reproduced.

Simultaneous Determination of 11 Appetite Suppressants in Weight-loss Functional Foods by Accelerated Solvent Extraction- High Performance Liquid Chromatography Tandem Mass Spectrometry / 分析化学

An analytical method based on high performance liquid chromatography tandem mass spectrometry has been developed for the determination of 11 appetite suppressants (fenfluramine,phenylpropanolamine,sibutramine,sertraline,rimonabant,bupropion,citalopram,fluoxetine,benfluorex,topiramate,zoni-samide). Various weight-loss functional foods were extracted under accelerated solvent extraction and separated on Waters Atlantis T3( 150 mm×2.1 mm,3μm) column. The analysis was carried out on HPLC-MS/MS by electrospray ionization using multiple reaction monitoring. Identification was achieved by ihe retention time and the ion ratio,quantification was done by the external standard curves. The limits of detection for the appetite suppressants were 0.05-4.0 mg/kg. The mean recoveries at the three spiked levels(low,middle,high) were 78.3% - 103. 6% ,with the intra-day precision less than 12% and the inter-day precision less than 15%. The method is reliable,sensitive,reproducible,and adapts to the determination of the appetite suppressants in different weight-loss functional foods.

OBESITY : A MODERN DAY PLAGUE.

Obesity is the presence of excess body fat. Unfortunately obesity is taken as a mere cosmetic problem and not a medical one. Today obesity is being 'dealt' with more by the self-proclaimed fitness experts running the rapidly mushrooming fitness centres rather than by medical professionals. But rather than merely a cosmetic problem, obesity should be viewed as a disease because there are multiple biologic hazards at surprisingly low levels of excess fat With the rapid pace of industrialisation and economic progress, today more and more jobs are becoming sedentary and dietary patterns are also changing with a decline in the cereal intake and increase in the intake of sugar and fats. However, inherited physiologic differences in response to eating and exercise are also important factors. Treating obesity can often be a frustrating experience for both the physician and the patient because of the great difficulty in maintaining weight loss over the long term. However, a clear understanding of the causes of obesity and a treatment strategy based on a combination of diet, nutrition, education, exercise, behaviour modification and social support can go a long way in containing this 'modern day plague' before it acquires epidemic proportions.