[Implementation of a multi-interventional approach to improve medication safety in older hospitalized patients: Feasibility and impact on 30-day rehospitalization rate]. / Mise en place d'une procédure multi-interventionnelle de prise en charge médicamenteuse chez la personne âgée hospitalisée : faisabilité et efficacité sur la réhospitalisation à 30jours.

BACKGROUND: The impact of a multi-interventional approach for medication safety (MIMS) on rehospitalization rate have been inconstant in the literature. This would be due to difficulty in implementing the interventions and insufficient information transmission at discharge. The purpose of this study was to determine the effect of a MIMS on the 30-day rehospitalization rate after discharge from an acute geriatric unit (AGU). METHOD: This was a single-center interventional randomized controlled trial that included patients hospitalized in an AGU and were at least 75 years old. The intervention group benefited from a MIMS including medication reconciliation at admission and at discharge, medication review, and standardized transmission of hospital's medication changes sent to community practitioners (general practitioners and pharmacists) at discharge. The control group benefited from the usual approach applied in the AGU. RESULTS: One hundred nine patients (mean age 87,5±6,1 years) were included. At intention-totreat analysis, the rehospitalization rate was 30% in the intervention group and 15,2% in the control group. The difference was non-significant before and after adjustments (P=0,27 and 0,28 respectively). However, the intervention protocol was not effectively completed in 40% of patients in the intervention group and no intervention was performed in 10%. CONCLUSION: The implementation of a MIMS in an AGU showed a non-significant decrease in the number of rehospitalizations. Other indicators should be analysed, such as the reason for rehospitalisation or the maintenance of treatment at 30 days.

Hip fractures and characteristics of living area: a fine-scale spatial analysis in France.

We investigated the association between hip fracture incidence and living area characteristics in France. The spatial distribution of hip fracture incidence was heterogeneous and there was a significant relationship between social deprivation, urbanization, health access, and hip fracture risk. INTRODUCTION: Several studies have shown great disparities in spatial repartition of hip fractures (HF). The aim of the study was to analyze the association between HF incidence and characteristics of the living area. METHODS: All patients aged 50 or older, living in France, who were hospitalized for HF between 2012 and 2014 were included, using the French national hospital discharge database. Standardized incidence ratio (SIR) was calculated for each spatial unit and adjusted on age and sex. An ecological regression was performed to analyze the association between HF standardized incidence and ecological variables. We adjusted the model for neighborhood spatial structure. We used three variables to characterize the living areas: a deprivation index (French-EDI); healthcare access (French standardized index); land use (percentage of artificialized surfaces). RESULTS: A total of 236,328 HF were recorded in the French hospital national database, leading to an annual HF incidence of 333/100,000. The spatial analysis revealed geographical variations of HF incidence with SIR varying from 0.67 (0.52; 0.85) to 1.45 (1.23; 1.70). There was a significant association between HF incidence rates and (1) French-EDI (trend p = 0.0023); (2) general practitioner and nurse accessibility (trend p = 0.0232 and p = 0.0129, respectively); (3) percentage of artificialized surfaces (p < 0.0001). CONCLUSION: The characteristics of the living area are associated with significant differences in the risk of hip fracture of older people.

Correction to: Secondary prevention of osteoporotic fractures: evaluation of the Lille University Hospital's Fracture Liaison Service between January 2016 and January 2018.

The original version of this article, published on 5 June 2019, an author's name was misspelled.

Secondary prevention of osteoporotic fractures: evaluation of the Lille University Hospital's Fracture Liaison Service between January 2016 and January 2018.

The purpose of this study was to assess the performance of our Fracture Liaison Service (FLS) over a period of 2 years. Osteoporosis medication was prescribed for 243 patients, and zoledronic acid was the main drug prescribed (60.2%). INTRODUCTION: A Fracture Liaison Service (FLS) was implemented at Lille University Hospital in 2016. The main purpose of this study was to assess the performance of the FLS using criteria proposed by the International Osteoporosis Foundation (IOF). METHODS: The criteria used were patient identification, patient evaluation, post-fracture assessment timing, vertebral-fracture identification, blood and bone mineral density (BMD) testing, falls prevention, multifaceted health and lifestyle risk-factor assessment, and medication initiation and review. RESULTS: Between January 2016 and January 2018, 736 patients (≥ 50 years old) with a recent history of fragility fracture (≤ 12 months) were identified. The identification rate for hip fractures was 74.2%. However, patient evaluation for all type of fractures was quite low (30.3%) since many patients failed to attend the FLS unit. The reasons for non-attendance were refusal, agreed but subsequently failed to attend, and still waiting to be seen. In all, 256 patients (76.6% female, mean (SD) age 74.3 (11.0) years) were seen at the FLS. Mean (SD) post-fracture assessment timing was 13.3 (9.3) weeks. Of the 139 patients seen for a non-vertebral fracture, 103 were assessed for vertebral fractures, and at least one new vertebral fracture was found in 45 of them (43.7%). Osteoporosis medication was prescribed for 243 (94.9%) patients. The main osteoporosis drug prescribed was zoledronic acid (60.2%). CONCLUSIONS: Secondary prevention of osteoporotic fractures has improved since the implementation of the FLS. However, patient identification, patient evaluation, and post-fracture assessment timing still need to be improved.

[Changes in drug management of Alzheimer's disease in nursing homes: Impact of the media campaign against specific drugs for Alzheimer's disease]. / Évolution de la prise en charge médicamenteuse de la maladie d'Alzheimer en EHPAD : impact de la campagne médiatique contre les médicaments spécifiques de la maladie d'Alzheimer.

CONTEXT: Alzheimer's disease is a common disease in nursing homes. Evolution is constantly negative and specific treatments, which are only symptomatic, are subject to controversy. In a context of media exposure, the Transparency Committee of the Haute Autorité de santé (HAS) downgraded their medical service in October 2011, seeing it as weak. AIM: Assess the evolution of the consumption of specific treatments for Alzheimer's disease; assess changes in the quality of monitoring in specific consultation. METHODS: This is a retrospective and descriptive study, cross-sectional in three times (T0 January 2011, T1 October 2011 and T2 June 2012), in 6 nursing homes of Lille and its surroundings. RESULTS: In total, 262 residents with dementia and present at least once during the three times of the study were included. Their mean age was 85.8 years. Among them, 40 % had Alzheimer's disease clearly identified. At T0, 76.7 % of patients present who were supposed to receive a specific treatment of Alzheimer's disease were actually receiving such treatment, 73.6 % at T1 and 71.6 % at T2. After 17 months of observation, the discontinuation rate of anticholinesterase was 34 %, 24 % for anti-glutamate. The monitoring in specific consultations decreased slightly between the three stages. CONCLUSION: Our work did not show major impact of the media campaign against specific drugs for Alzheimer's disease. There is however a trend towards a decrease of their consumption in people with dementia living in nursing homes with no obvious link between monitoring in specific consultation and specific prescription. This trend would ask to be confirmed by a study on a larger scale.

Systematic skin examination in an acute geriatric unit: skin cancer prevalence.

BACKGROUND: Ageing is a determining factor in skin cancer, but the incidence and prevalence of skin cancer in elderly patients are not known. AIM: To determine the prevalence of skin cancers in elderly patients and to assess their associated geriatric syndromes. METHODS: Between January and April 2013, all consecutive incident patients hospitalized in the Acute Geriatric Unit of Lille University Hospital underwent a geriatric assessment and a systematic dermatological examination. A biopsy was taken whenever there was any lesion with suspicion of malignancy. RESULTS: In total, 204 patients (mean age 85.4 years) were included, and 16 cutaneous biopsies were taken from 15 patients. Histological examination confirmed skin cancer in 11 biopsies from 10 patients: 9 basal cell carcinomas, 1 squamous cell carcinoma (SCC) and 1 malignant lentigo. The prevalence of skin cancer was 4.9%. The geriatric assessment revealed severe geriatric syndromes in the 10 patients with skin cancer: severe dependence (8/10), possible cognitive impairment (10/10), and moderate or severe malnutrition (5/10). CONCLUSIONS: The prevalence of skin cancer is high in frail elderly patients. The association of severe geriatric syndromes suggests that close collaboration between geriatricians and dermatologists is essential to optimize the treatment of skin carcinoma in elderly patients.

Use of a clustering method to describe the clinical profiles of older fallers: the value of a multidisciplinary consultation.

OBJECTIVES: The population of older adults is particularly heterogeneous with regard to frailty and the risk of falling, the two of which are linked. We conducted an exploratory, analysis (with no preconceived ideas) of data collected during multidisciplinary falls consultations (MFCs), to identify people with similar profiles. MATERIALS AND METHODS: We performed an observational, multicentre study of older patients (aged 75 and over) having been evaluated in an MFC. We excluded adults with a Mini Mental State Examination score < 14/30, an activities of daily living score < 4/6, or an unstable medical condition. Each participant underwent a clinical interview, impedancemetry, and a physical activity assessment (a questionnaire, and use of an activity tracker on 5 consecutive days). The K-means method and ascending hierarchical clustering were used to identify clusters of people with common characteristics. RESULTS: Of the 106 participants, the median [IQR] mean number of falls in the previous 6 months was 1 [2]. Three functional clusters were identified: (i) fallers with poor mobility, difficulty getting up off the ground after a fall, and using a mobility aid for walking; (ii) an intermediate sedentary group with a gait speed of ~ 0.6 m s-1, and (iii) active people with a timed "up and go" test time below 15 s and a gait speed above 0.8 m s-1. CONCLUSIONS: The population of older fallers referred for an MFC is heterogeneous. The presence of certain clinical characteristics enabled the definition of three patient clusters, which might help physicians to determine the most appropriate care objectives and pathways.

The Care Coordinator's Tasks During the Implementation of an Integrated Care Pathway for Older Patients: A Qualitative Study Based on the French National "Health Pathway of Seniors for Preserved Autonomy" Pilot Program.

Background: Although integrated care and care coordination are known to be beneficial for older adults' population, the specific tasks of a Care Coordinator (CC) for integrated care pathways for this population have not been studied in detail. Setting & Subjects: The French national pilot program PAERPA provided an integrated care pathway for older adults. In North France, a CC was recruited to support patients and professionals. Objectives: (i) To analyse the CC's tasks in an integrated care pathway for older patients, and (ii) to record perceptions on the CC's tasks among the participating general practitioners (GP) and community pharmacists. Design & Methods: Qualitative, two-phase study: (i) Task analysis of the CC's tasks, to compare the planned and actual tasks; (ii) semi-structured interviews among GPs and community pharmacists involved in the pathway. Results: (i) The task analysis showed that the CC's actual tasks differed from planned tasks. The CC was only meant to be involved in the early stages of the process; actually, the CC undertook more or even unforeseen tasks in coordination, communication, and administrative support throughout the care pathways. (ii) The 28 interviewed healthcare professionals considered the CC's tasks to be essential to the success of pathways. They appreciated the CC's administrative support. However, CC's tasks related to interprofessional communication, and patient and family information, were controversially perceived among GPs and pharmacists. Conclusions: The CC's tasks in an integrated care pathway for older adults showed that the CC's overall workload was greater than expected and appreciated by healthcare professionals.

[Neurological diseases detected in the Lille Multidisciplinary Falls Consultation]. / Les maladies neurologiques repérées lors de la consultation multidisciplinaire de la chute du CHRU de Lille (France).

BACKGROUND: People with neurological disorders including stroke, dementia, Parkinson's disease, and polyneuropathy are known to have an increased risk of falls. OBJECTIVE: To evaluate the prevalence and nature of neurological risk factors among the patients attending the Multidisciplinary Falls Consultation of the University Hospital of Lille (France), and to analyze the characteristic features of patients termed "neurological fallers" with neurological risk factors. METHODS: The study included 266 consecutive patients who were initially assessed by a geriatrician, a neurologist and a physiatrist, and again, six months later, by the same geriatrician. RESULTS: Two out of three patients had neurological signs that can be regarded as neurological risk factors of falling. These neurological signs had not been diagnosed before the consultation in 85% of cases. The most common conditions were deficit of lower extremity proprioception (59% of patients) and cognitive impairment (43%). The most frequently evoked neurological diseases were dementia (40% of patients), polyneuropathy (17%) and stroke (8%). Compared with other patients, "neurological fallers" were more frequently living in a nursing home, had lower ADL and MMSE scores at baseline, had experienced more falls in the six preceding months, had a lower probability of having a timed Up-and-Go test less than 20 seconds and a single limb stance equal to 5 seconds. In the follow-up, "neurological fallers" reported hospitalizations more often. CONCLUSION: The findings show that a large proportion of old persons presenting at the Multidisciplinary Falls Consultation have unrecognized neurological disorders. Comprehensive neurological examination including an evaluation of cognition is required in every elderly faller.

[Specificity of epileptic seizures in the elderly: A proposed electro-clinical scale]. / Spécificités des crises d'épilepsie chez le sujet âgé : proposition d'un score électro-radioclinique d'orientation.

Diagnosis of epileptic seizure may be difficult in older patients because seizure manifestations are often unusual: confusion, paresis... and because there are multiple differential diagnoses (syncope, transient ischemic attack, transient global amnesia...). To promote and facilitate the diagnosis of seizures in the elderly, neurologists and gerontologists must work together and focus their strategy on two points: firstly, the knowledge of the specific presentation of seizures in elderly patients, and secondly, the adoption of a reasoning based on seizures and not epileptic syndromes. A multidisciplinary group worked on epilepsy of the elderly to elaborate an electro-clinical score which aims to help establish the diagnosis of epilepsy in elderly patients in different clinical settings. This electro-clinical score is based on a systematic review of scientific literature and the recommendations are explicitly linked to supporting evidence. Further, clinical validation of the electro-clinical score is required.

[Swallowing disorders, pneumonia and respiratory tract infectious disease in the elderly]. / Troubles de la déglutition du sujet âgé et pneumopathies en 14 questions/réponses.

Swallowing disorders (or dysphagia) are common in the elderly and their prevalence is often underestimated. They may result in serious complications including dehydration, malnutrition, airway obstruction, aspiration pneumonia (infectious process) or pneumonitis (chemical injury caused by the inhalation of sterile gastric contents). Moreover the repercussions of dysphagia are not only physical but also emotional and social, leading to depression, altered quality of life, and social isolation. While some changes in swallowing may be a natural result of aging, dysphagia in the elderly is mainly due to central nervous system diseases such as stroke, parkinsonism, dementia, medications, local oral and oesophageal factors. To be effective, management requires a multidisciplinary team approach and a careful assessment of the patient's oropharyngeal anatomy and physiology, medical and nutritional status, cognition, language and behaviour. Clinical evaluation can be completed by a videofluoroscopic study which enables observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. The treatment depends on the underlying cause, extent of dysphagia and prognosis. Various categories of treatment are available, including compensatory strategies (postural changes and dietary modification), direct or indirect therapy techniques (swallow manoeuvres, medication and surgical procedures).

Factors Associated with Alzheimer's Disease: An Overview of Reviews.

Alzheimer's disease (AD) is a frequent pathology, with a poor prognosis, for which no curative treatment is available in 2018. AD prevention is an important issue, and is an important research topic. In this manuscript, we have synthesized the literature reviews and meta-analyses relating to modifiable risk factors associated with AD. Smoking, diabetes, high blood pressure, obesity, hypercholesterolemia, physical inactivity, depression, head trauma, heart failure, bleeding and ischemic strokes, sleep apnea syndrome appeared to be associated with an increased risk of AD. In addition to these well-known associations, we highlight here the existence of associated factors less described: hyperhomocysteinemia, hearing loss, essential tremor, occupational exposure to magnetic fields. On the contrary, some oral antidiabetic drugs, education and intellectual activity, a Mediterranean-type diet or using Healthy Diet Indicator, consumption of unsaturated fatty acids seemed to have a protective effect. Better knowledge of risk factors for AD allows for better identification of patients at risk. This may contribute to the emergence of prevention policies to delay or prevent the onset of AD.

[Aging: role and control of glycation]. / Vieillissement: rôle et contrôle de la glycation.

PURPOSE: Advanced glycation end-products (AGEs) accumulate in aging tissues and organs during rheumatoid arthritis and Alzheimer disease. These aging toxins are especially involved in cell alteration during diabetes mellitus (glycotoxin) and renal failure (uremic toxin). AGEs participate to the endothelial dysfunction leading to diabetic macro but also micro-angiopathy. AGEs binding to cell receptors are critical steps in the deleterious consequences of AGE excess. AGE-receptor activation altered cell and organ functions by a pro-inflammatory, pro-coagulant and pro-fibrosis factors cell response. CURRENT KNOWLEDGE AND KEY POINTS: Non-enzymatic glycation and glycoxidation with glucose auto-oxidation represent the two main pathways resulting in AGE formation. No exclusive AGE classification is actually available. Pathophysiological mechanisms are described to explain AGE toxicity. AGEs bind to cell receptors inducing deleterious consequences such as endothelial dysfunction after endothelial RAGE activation. AGEs can also have deleterious effects through glycated protein accumulation or in situ protein glycation. FUTURE PROSPECTS AND PROJECTS: Many in vitro or animal studies demonstrated that AGE deleterious effects can be prevented by glycation inhibitors, AGE cross-link breakers or AGE-RAGE interaction inhibition. New molecules are actually studied as new strategy to prevent or treat the deleterious effects of these aging toxins.

[Lung cancer in the elderly subject]. / Cancer bronchique du sujet âgé.

INTRODUCTION: In France, the average age for the diagnosis of bronchial carcinoma is 64. It is 76 in the population of over 70. In fact, its incidence increases with age linked intrinsic risk of developing a cancer and with general ageing of the population. Diagnosis tools are the same for elderlies than for younger patients, and positive diagnosis mainly depends on fibreoptic bronchoscopy, complications of which being comparable to those observed in younger patients. STATE OF THE ART: The assessment of dissemination has been modified in recent years by the availability of PET scanning which is increasingly becoming the examination of choice for preventing unnecessary surgical intervention, a fortiori in elderly subjects. Cerebral imaging by tomodensitometry and nuclear magnetic resonance should systematically be obtained before proposing chirurgical treatment. An assessment of the general state of health of the elderly subject is an essential step before the therapeutic decision is made. This depends on the concept of geriatric evaluation: Geriatric Multidimensional Assessment, and the Comprehensive Geriatric Assessment which concerns overall competence of the elderly. PERSPECTIVES: This is a global approach that allows precise definition and ranking of the patient's problems and their impact on daily life and social environment. Certain geriatric variables (IADL, BADL, MMSE, IMC etc) may be predictive of survival rates after chemotherapy or the incidence of complications following thoracic surgery. The main therapeutic principles for the management of bronchial carcinoma are applicable to the elderly subject; long term survival without relapse after surgical resection is independent of age. Whether the oncological strategy is curative or palliative, the elderly patient with bronchial carcinoma should receive supportive treatments. They should be integrated into a palliative programme if such is the case. In fact, age alone is not a factor that should detract from optimal oncological management. CONCLUSIONS: The development of an individual management programme for an elderly patient suffering from bronchial carcinoma should be based on the combination of oncological investigation and comprehensive geriatric assessment.

Alcohol and psychotropic drugs: risk factors for orthostatic hypotension in elderly fallers.

We assess orthostatic hypotension (OH) prevalence in elderly fallers and determine OH-associated risk factors in this patient population. A monocentric prospective study at Lille University Hospital Falls Clinic included 833 consecutive patients who had fallen or were at high risk of falls and who were assessed for the presence of OH. Among 833 patients aged 80.4±7.4 years, OH was found in 199 subjects (23.9% of cases). Multivariate analysis showed that selective serotonin reuptake inhibitors (odds ratio (OR) 2.42, 95% confidence interval (CI): 1.56-3.75), serotonin-norepinephrine reuptake inhibitors (OR 5.37, 95% CI: 1.93-14.97), Parkinsonian syndrome (OR 2.54, 95% CI: 1.54-4.19), excessive alcohol consumption (OR 2.17, 95% CI: 1.32-3.56), meprobamate (OR 2.65, 95% CI: 1.12-6.25) and calcium channel blockers (OR 1.79, 95% CI: 1.16-2.76) were all risk factors for OH. In contrast, angiotensin receptor blockers (OR 0.52, 95% CI: 0.30-0.91) appeared to be protective factors against OH. This study demonstrates that a systematic investigation should be made in all elderly fallers and those at high risk of falls to detect the presence of OH. In OH patients, in addition to the usual predisposing factors, excessive alcohol consumption and psychotropic drug intake-in particular, the intake of serotonergic antidepressants-should be taken into account as potential risk factors.

[Evaluation of pulmonary function in the elderly. Intergroupe Pneumo Gériatrie SPLF-SFGG]. / Evaluation de la fonction respiratoire chez le sujet âgé. Intergroupe Pneumo Gériatrie SPLF-SFGG.

Aging is associated with a progressive decrease in lung function. As a consequence of aging, individual's reserve is diminished, but this decrease is heterogeneous between individual subjects. Many factors are involved in the overall decline in lung function. The prevalence of asthma in the elderly is estimated between 6 and 10%. Mortality due to COPD is increasing, especially among older subjects. Older subjects are at an increased risk of developing chronic diseases such as Parkinson's disease, which can have consequences for lung function. Under-nutrition is also common in the elderly and can produce sarcopenia and skeletal muscle dysfunction. The presentation of respiratory disorders may differ in the elderly, especially because of a lack of perception of symptoms such as dyspnea. The impact of bronchodilatators or corticosteroids on respiratory function has not been studied in the elderly. Drugs usually used for the treatment of hypertension or arrhythmias, which are often observed with aging, can have pulmonary toxicity. There is no difference between functional evaluation in younger and older subjects but it is more difficult to find predicted values for older patients. Performing pulmonary function tests in older patients is often difficult because of a higher prevalence of cognitive impairment and/or poor coordination. When assessing pulmonary function in the elderly, the choice of tests will be depend on the circumstances, with the use of voluntary manoeuvres dependent on the condition of the patient.

[Drug delivery systems: a real therapeutic advance]. / Les systèmes de délivrance des médicaments: un réel progrès pour la thérapeutique.

Established at the request of the Research Committee of the French National Academy of Pharmacy, this report on drug delivery systems (DDS) is a summary of information gathered by interviewing leaders in the pharmaceutical community and from the international literature. This report includes: a rapid recall of pharmaceutical formulations and changes over the last decades; a definition of DDS, indications on their evolution and a discussion on their contribution to drug administration; information on firms specialized in the elaboration of DDS, their interactions with the drug industry and the current and future market for DDS; a presentation of the potential offered by DDS for the drug industry; a discussion on technical, regulatory, and economic issues which could obstruct drug administration using a DDS; a description of certain DDS selected for their therapeutic contributions and a brief presentation of perspectives; a presentation of certain recommendations for organizations concerned with DDS.

Liposomes bearing platelet proteins: a model for surface functions studies.

An improved procedure for the direct transfer of membrane proteins from human platelets to liposomes involving the treatment of platelets with linolenic acid was developed. The transfer of platelet proteins to liposomes prepared from the mixture of L-alpha-dimyristoyl-phosphatidylcholine/sphingomyelin in the molar ratio 80/20 appeared to be significantly enhanced compared with liposomes prepared from the same components mixed in other ratios. A wide range of platelet proteins was transferred, the most important being GPIb (170 kDa), GPIIb/IIIa (135 and 110 kDa). GPIV (90 kDa), GPIX (24 kDa) and the serotonin transporter (68 kDa). The recognition interactions between these proteoliposomes and specific protein antibodies clearly indicate that the non-invasive procedure used in this study ensured the reproducible transfer of platelet proteins without essentially altering their original conformation. The obtained results reveal also that the affinity of proteoliposomes to bind paroxetin was virtually the same as that of the native serotonin transporter. These results provide an indication of the possible use of such proteoliposomes as models to study at the molecular level the interaction of these proteins with their ligands.

Factors influencing macrophage activation by muramyl peptides: inhibition of NO synthase activity by high levels of NO.

Treatment with muramyldipeptide (MDP) or a lipophilic derivative (MTP-Chol) included in nanocapsules renders macrophages cytostatic towards tumor cells. At the same time, nitric oxide (NO) synthase (EC 1.14.23) activity is induced, as determined by measurement of the two end products of the reaction (nitrite and L-citrulline). The objective of this study was to investigate some factors which might influence this activation and explain the decreased response observed at high nanocapsule concentrations. The glucose content of the medium did not seem to be limiting. Addition of indomethacin decreased nitrite production in the effector phase, suggesting a role for prostaglandins in the maintenance of the activated state. We also tested the hypothesis that NO itself might regulate inducible nitric oxide synthase activity. The addition of NO donors (SIN-1 and nitrosoglutathione) or superoxide dismutase to cultures of activated macrophages inhibited the NO synthase activity. Since these NO donors were non toxic towards macrophages, these observations indicate clearly that the addition of exogenous NO to that formed by the enzymatic reaction can cause inhibition of the inducible NO synthase.