IgG4-related hypophysitis: a retrospective cohort study.

PURPOSE: IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for patients with histologically proven IgG4-related hypophysitis. METHODS: A prospectively maintained electronic database was searched over a 14-year period from 1 January 2007 to 31 December 2020 at a single academic centre to identify all patients with a histological diagnosis of IgG4-RH. A retrospective case note review from electronic health records was conducted for each case to extract data on their presentation, management and outcomes. RESULTS: A total of 8 patients (5 male) with a median age of 51 years were identified. The most common presenting symptoms were headache (4/8; 50%), fatigue (3/8; 37.5%) and visual impairment (2/8; 25%). Three patients were initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, ultimately all patients underwent transsphenoidal surgery. Post-operative changes included radiological reduction in pituitary mass in all patients that had imaging (7/7; 100%), improvement in vision (1/2; 50%), residual thick pituitary stalk (5/7; 71.4%), persistent anterior hypopituitarism (4/8; 50%) and panhypopopituitarism including diabetes insipidus (3/8; 37.5%). CONCLUSIONS: IgG4-RH is an increasingly recognised entity presenting with a variety of symptoms and signs. Clinical presentation is similar to other forms of hypophysitis. It is therefore important to consider IgG4-RH as a differential and to have a low threshold for pituitary biopsy, the diagnostic gold standard. The diagnosis of IgG4-RH will guide decisions for additional workup for IgG4-related disease, multi-disciplinary team involvement and follow-up.

ADAP is a possible negative regulator of glucosinolate biosynthesis in Arabidopsis thaliana based on clustering and gene expression analyses.

Glucosinolates (GSLs) are plant secondary metabolites consisting of sulfur and nitrogen, commonly found in Brassicaceae crops, such as Arabidopsis thaliana. These compounds are known for their roles in plant defense mechanisms against pests and pathogens. 'Guilt-by-association' (GBA) approach predicts genes encoding proteins with similar function tend to share gene expression pattern generated from high throughput sequencing data. Recent studies have successfully identified GSL genes using GBA approach, followed by targeted verification of gene expression and metabolite data. Therefore, a GSL co-expression network was constructed using known GSL genes obtained from our in-house database, SuCComBase. DPClusO was used to identify subnetworks of the GSL co-expression network followed by Fisher's exact test leading to the discovery of a potential gene that encodes the ARIA-interacting double AP2-domain protein (ADAP) transcription factor (TF). Further functional analysis was performed using an effective gene silencing system known as CRES-T. By applying CRES-T, ADAP TF gene was fused to a plant-specific EAR-motif repressor domain (SRDX), which suppresses the expression of ADAP target genes. In this study, ADAP was proposed as a negative regulator in aliphatic GSL biosynthesis due to the over-expression of downstream aliphatic GSL genes (UGT74C1 and IPMI1) in ADAP-SRDX line. The significant over-expression of ADAP gene in the ADAP-SRDX line also suggests the behavior of the TF that negatively affects the expression of UGT74C1 and IPMI1 via a feedback mechanism in A. thaliana.

Safety and effectiveness of a biosimilar biphasic insulin in the management of diabetes mellitus during routine clinical practice in Asian patients.

INTRODUCTION: Biosimilar insulins have the potential to increase access to treatment among patients with diabetes mellitus (DM), reduce treatment costs, and expand market competition. There are no published studies evaluating the performance of biosimilar insulins in routine clinical practice in Asia. This study assessed the safety and effectiveness of biphasic isophane insulin injection in Malaysian DM patients. MATERIALS AND METHODS: In this open label, single-arm, observational, post marketing study, patients received biphasic isophane insulin injection as per the Prescribing Information; and were assessed for safety (adverse events including hypoglycaemia), effectiveness (glycosylated haemoglobin [HbA1c]; fasting blood sugar, [FBS]; and patient's condition by patient and physician) over a period of 24 weeks. RESULTS: Adult male and female diabetes patients (N=119; type 2 DM, n=117) with a mean (SD) diabetes duration of 13 years were included. No new safety signals have been identified. Significant reduction in HbA1c was observed at weeks 12 and 24 (mean [SD] - baseline: 9.6% [1.9]; Week 12: 9.0% [1.7] and at Week 24: 9.1% [1.7]; p < 0.001). There were 10 serious and 9 non-serious adverse events reported in the study. Expected mild events included hypoglycaemia and injection site pruritus. However, the majority of the adverse events were non-study drug related events. No deaths were reported during the study. DISCUSSION: Biphasic isophane insulin injection was well tolerated with no new safety concerns. It was found effective in post- marketing studies conducted in routine clinical settings when administered in DM patients in this study.

Management of prediabetes in Malaysian population: An experts' opinion.

INTRODUCTION: Prediabetes, typically defined as blood glucose levels above normal but below diabetes thresholds, denotes a risk state that confers a high chance of developing diabetes. Asians, particularly the Southeast Asian population, may have a higher genetic predisposition to diabetes and increased exposure to environmental and social risk factors. Malaysia alone was home to 3.4 million people with diabetes in 2017; the figure is estimated to reach 6.1 million by 2045. Developing strategies for early interventions to treat prediabetes and preventing the development of overt diabetes and subsequent cardiovascular and microvascular complications are therefore important. METHODS: An expert panel comprising regional experts was convened in Kuala Lumpur, for a one-day meeting, to develop a document on prediabetes management in Malaysia. The expert panel comprised renowned subject-matter experts and specialists in diabetes and endocrinology, primary-care physicians, as well as academicians with relevant expertise. RESULTS: Fifteen key clinical statements were proposed. The expert panel reached agreements on several important issues related to the management of prediabetes providing recommendations on the screening, diagnosis, lifestyle and pharmacological management of prediabetes. The expert panel also proposed changes in forthcoming clinical practice guidelines and suggested that the government should advocate early screening, detection, and intensive management of prediabetes. CONCLUSION: This document provides a comprehensive approach to the management of prediabetes in Malaysia in their daily activities and offer help in improving government policies and the decision-making process.

Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: current evidence and challenges for clinical implementation.

The clinical response to sulphonylurea, an oral antidiabetic agent often used in combination with metformin to control blood glucose in type 2 diabetes (T2DM) patients, has been widely associated with a number of gene polymorphisms, particularly those involved in insulin release. We have reviewed the genetic markers of CYP2C9, ABCC8, KCNJ11, TCF7L2 (transcription factor 7-like 2), IRS-1 (insulin receptor substrate-1), CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP (nitric oxide synthase 1 adaptor protein) genes that predict treatment outcomes of sulphonylurea therapy. A convincing pattern for poor sulphonylurea response was observed in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, limitations in evaluating the available studies including dissimilarities in study design, definitions of clinical end points, sample sizes and types and doses of sulphonylureas used as well as ethnic variability make the clinical applications challenging. Future studies need to address these limitations to develop personalized sulphonylurea medicine for T2DM management.

Emergency laparoscopy in underserved settings: optimizing diagnosis and management of appendicitis with ruptured hemorrhagic ovarian cyst.

Introduction and importance: Laparoscopy is an established widely available technique for diagnosis and management. However, due to its high maintenance and expensive use, it is not readily available in emergency settings especially in underserved area hospitals. The coincidence of gynecologic and nongynecologic surgical emergencies incurs a diagnostic dilemma especially in women of reproductive age presenting with acute abdominal pain. Case presentation: This article is a case report about a woman presenting with acute abdominal pain in an underserved area and diagnosed as appendicitis. Clinical discussion: Emergency laparoscopy is so rare in underserved areas due to its high maintenance costs as well as the lack of availability of well-trained surgeons and personnel. The exceptional availability of emergency laparoscopy in her case has allowed the codiagnosis of a ruptured hemorrhagic ovarian cyst with the optimal surgical management preventing the complications that could have occurred from misdiagnosing the coincident ruptured hemorrhagic cyst. Conclusion: Emergency laparoscopy is not always available in such clinical settings and has, in our case, optimized the management and prevented an undiagnosed ruptured hemorrhagic cyst together with its complications.

Importance of screening for macroprolactin in all hyperprolactinaemic sera.

INTRODUCTION: Prolactin (PRL) exists in different forms in human serum. The predominant form is monomeric PRL (molecular mass 23 kDa) with smaller amounts of big PRL (molecular mass 50-60 kDa) and at times macroprolactin (molecular mass 150-170 kDa). Macroprolactin, generally considered to be biologically inactive, accounts for the major part of prolactin in some patients. Different immunoassays for prolactin differ in reactivity with this macromolecular complex. AIM: The present study was undertaken to assess the incidence of macroprolactinaemia in our cohort of hyperprolactinemic patients. METHOD: 204 samples with hyperprolactinemia were evaluated for macroprolactinemia by polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). Recoveries ≤60% after PEG precipitation were considered to have macroprolactinaemia. RESULTS: A total of 43 (21%) of these patients had less than 60% recovery after PEG precipitation. GFC confirmed that in seven of these patients macroprolactin was the major part of the prolactin. Recoveries were < 40% PEG precipitation in these samples. Combined macro and hyperprolactinemia was observed in two samples and the recovery after PEG precipitation was >40% but ≤50%. The incidence of macroprolactinemia in our cohort of hyperprolactinaemic patients was noted to be 4.4%. CONCLUSION: Macroprolactin is a significant cause of misdiagnosis, unnecessary investigation, and inappropriate treatment and hence it is useful to screen all patients with high PRL levels with PEG precipitation and to apply GFC to samples with recoveries <50%.

The status of diabetes control in Malaysia: results of DiabCare 2008.

DiabCare Malaysia 2008 evaluated the current status of diabetes care in Malaysia as a continuation of similar cross-sectional studies conducted previously in 1997, 1998, 2001 and 2003. The current study recruited 1670 patients from general hospitals, diabetes clinics and referral clinics to study current scenario of diabetes management. We report the results of type 2 diabetic population who constituted 92.8% (n = 1549). Results showed deteriorating glycaemic control with mean HbA1c of 8.66 +/- 2.09% with only 22% of the patients achieving ADA target of < 7%. 80.3% of patients were hypertensive and 75% were on anti-hypertensive medication. 46% of patients had LDL levels > 2.6 mmol/L; 19.8% had triglycerides > 2.2 mmol/L; 27.4% had HDL < 1 mmol/L despite 85% of the patients being on lipid lowering agents. Microvascular, macrovascular and severe late complications were reported in 75%, 28.9% and 25.4% patients respectively. The rates of diabetic complications were cataract 27.2%, microalbuminuria 7%, neuropathy symptoms 45.9%, leg amputation 3.8% and history of angina pectoris was 18.4%. Quality of life evaluation showed that about one third of patients have poor quality of life. Also, there was poor adherence to diet, exercise and self testing of blood glucose. In conclusion, majority of the patients were still not satisfactorily controlled. There is an urgent need for effective remedial measures to increase adherence to practice guidelines and to educate both patients and healthcare personnel on importance of achieving clinical targets for metabolic control.

Reprocessing and reuse of single-use medical devices: a national survey of Canadian acute-care hospitals.

A national survey investigated the current practices of reprocessing and reusing single-use medical devices in Canadian acute-care hospitals. Our response rate was 72% (413 responses), and 28% of hospitals reprocess single-use devices. The results showed that Canadian hospital practices have not changed much in the past decade.

Clinical efficacy and cost-effectiveness of newborn screening for medium chain acyl-CoA dehydrogenase deficiency using tandem mass spectrometry.

OBJECTIVE: To determine the clinical efficacy and cost-effectiveness of newborn screening for MCADD using tandem mass spectrometry (MS/MS) compared with clinical diagnosis within the Canadian context. DESIGN AND METHODS: A systematic review of the clinical and economic literature was performed. For primary economic analysis, a decision-tree model was built based on the available information, the impact of newborn screening on the health care and the relevant Canadian data. RESULTS: Twenty-one clinical and two economic studies met the selection criteria. Mean incidence of MCADD was approximately 1:16,000. Clinical sensitivity and specificity were 100% and 99.99%, respectively. Screening significantly lowered morbidity and mortality. Both economic studies showed that screening for MCADD using MS/MS was cost-effective if willingness-to-pay was US 50,000 dollars. Our primary economic analysis showed that screening was cost-effective based on the cost-effective threshold of C 20,000 dollars per QALY. CONCLUSION: Screening consumes more resources than no screening but attains better health outcomes.

A combined case of macroprolactinoma, growth hormone excess and Graves' disease.

Thyrotoxicosis due to Graves disease is a relatively common endocrine disorder. The occurrence of a prolactinoma with co-secretion of growth hormone (GH) is on the other hand, rare. We report the rare co-existence of Graves' disease in a patient with macroprolactinoma and GH hypersecretion and describe the successful response to medical therapy with dopamine agonist and antithyroid therapy. We hypothesize that hyperprolactinaemia played a role in promoting autoimmune thyroid disease in our patient and that treatment of hyperprolactinaemia may have been important in suppressing autoimmune disease activity in Graves' disease. This case also reflects on the close and complex interactions between thyroid hormones, prolactin (PRL), GH and testosterone (T).

Integrated Simulation Framework for Toxicity, Dose Intensity, Disease Progression, and Cost Effectiveness for Castration-Resistant Prostate Cancer Treatment With Eribulin.

Quantitative model-based analyses are helpful to support decision-making in drug development. In oncology, disease progression/clinical outcome (DPCO) models have been used for early predictions of clinical outcome, but most of such approaches did not include adverse events or dose intensity. In addition, cost-effectiveness evaluations of investigational compounds are becoming increasingly important. Here, we developed an integrated model-based framework including relevant treatment effects for patients with castration-resistant prostate cancer treated with the anticancer agent eribulin. The framework included (i) a DPCO model relating prostate-specific antigen (PSA) dynamics to survival; (ii) models for adverse events including dose-limiting neutropenia and other graded toxicities; (iii) a model for Eastern Cooperative Oncology Group (ECOG) performance score; (iv) a model for dropout; (v) the consideration of cost effectiveness. The model allowed simulation of realistic treatment courses. Subsequently, simulations evaluating alternative treatment protocols or patient characteristics were performed in order to derive inferences on expected efficacy and cost effectiveness.

Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated With Eribulin.

Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant prostate cancer (CRPC) using historical phase II data of the anticancer agent eribulin. Disease progression was captured using the dynamics of prostate-specific antigen (PSA). For clinical outcome, overall survival (OS) was used. The model for PSA dynamics comprised parameters for baseline PSA (23.2 ng/ml, relative standard error (RSE) 16.5%), growth rate (0.00879 day(-1), RSE 12.6%), drug effect (0.241 µg·h·l(-1) day(-1), RSE 32.6%), and resistance development (0.0113 day(-1), RSE 44.3%). OS was modeled according to a Weibull distribution. Predictors for survival included model-predicted PSA time to nadir (TTN), PSA growth rate, Eastern Cooperative Oncology Group (ECOG) score, and baseline PSA. The developed framework can be considered to support informative design and analysis of drugs developed for CRPC.

Inverted Papilloma Originating Primarily from the Nasolacrimal Duct: A Case Report and Review of the Pertinent Literature.

Introduction. Inverted papilloma (IP) is an uncommon, benign yet aggressive neoplasm characterised by high recurrence rates and tendency towards malignant transformation. The majority of IP cases originate in the ethmoid region, lateral wall of the nasal fossa, and maxillary sinus. The authors report a case of an IP originating primarily from the nasolacrimal duct (NLD). Case. A 69-year-old Caucasian gentleman presented with a lump in his right medial canthal region, epiphora, and discharge bilaterally. Radiological investigation revealed a well-defined, heterogeneous mass within the proximal NLD eroding the bony canal, protruding into the middle meatus and into the right orbit. The tumour was excised en bloc utilizing a combined external and endoscopic approach based on its location. Histology revealed hyperplastic ribbons of basement membrane-enclosed epithelium growing endophytically into the underlying stroma with no evidence of invasive malignancy. The patient made an uneventful recovery with unchanged visual acuity and normal extraocular movements. Conclusion. The case demonstrates variability within the sinonasal tract that IP can develop and the individuality of each case necessitating tailored operative techniques for complete excision whilst minimising recurrence rates. We also present a combined endoscopic approach for the en bloc resection of a NLD IP with no clinical recurrence at 15-month follow-up.

A Multicenter Experience from Lebanon in Childhood and Adolescent Acute Myeloid Leukemia: High rate of Early Death in Childhood Acute Promyelocytic Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a disease with marked heterogeneity. Despite major improvement in outcome, it remains a life-threatening malignancy. Demographic and clinical data on pediatric AML is lacking among the Lebanese population. PURPOSE: We aimed to identify clinical, molecular and outcome data in children with AML in Lebanon. METHODS: A retrospective chart review of children with AML diagnosed in three Lebanese hospitals during the past 8 years was conducted. RESULTS: From May 2002 through March 2010, we identified 24 children with AML in Saint George Hospital University Medical Center, University Medical Center Rizk Hospital, and Abou-Jaoude Hospital. Males and females were equally represented; median age at diagnosis was 9 years (range 1-24) and median WBC at diagnosis was 31 × 10(9)/L (range: 2.1-376 × 10(9)/L). Twenty five percent of patients (6 out of 24) had acute promyelocytic leukemia (APL). Karyotype was normal in 33% of patients; t(8;21), inv (16), t(8;9), t(7;11), t(9;11), complex chromosomal abnormality, monosomy 7 and trisomy 8 were the most common cytogenetic abnormalities encountered. Patients were treated on different European and North American protocols. Twelve patients (50%) achieved morphologic CR after cycle 1, 6 of them (50%) had bone marrow relapse within 11 months from diagnosis. Nine patients underwent allogeneic stem cell transplant, and 3 of them are alive at 5 years post-transplant. Early death rate was 16.6% of patients, mainly those with APL and a presenting WBC > 10 × 10(9)/L. Fifty per cent of APL patients had an early death due to DIC despite starting ATRA therapy. Overall, median survival for AML patients who died from disease progression was 25.8 months (range: 1-60 months). Overall disease-free survival was 30.4%. Patients < 10 years of age had a 50% survival rate compared to 0% in patients > 10 years. CONCLUSIONS: Our report highlights the needs in Lebanon for better supportive care of children with APL, including faster ATRA administration and, aggressive transfusions, easy access to stem cell transplant for high-risk AML patients and the need for a national homogenous treatment strategy for children with AML.

A nationwide non-interventional epidemiological data registry on myelodysplastic syndromes in Lebanon.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral blood cytopenias, blood cells dysplasia, and increased risk for progression to acute leukemia.Physicians should be vigilant in diagnosing MDS and should be aware of the contemporary therapies that are always in progress. Most of the data on MDS epidemiology and management comes from developed countries. The incidence and features of MDS in the Arab countries, among them Lebanon, are not known. We undertook a nationwide epidemiological registry study of all newly diagnosed MDS cases through 2010-2011. Patients were referred by 21 hematologists/oncologists practicing in 17 hospitals and medical centers distributed across the entire country. 58 patients (29 males and 29 females) with confirmed MDS were included. The calculated incidence rate of MDS was 0.71 per 100,000 people. The median age at diagnosis was 73 years (range 16-86). The most common complaints on presentation were fatigue (70.7%), weakness (60.3%) and pallor (43.1%). Most patients were diagnosed as refractory anemia with excess blasts (RAEB; 36.2%) and refractory cytopenia with multilineage dysplasia (RCMD; 32.8%). This paper constitutes the first epidemiological report on the incidence and specific subtypes of MDS in Lebanon.

Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum.

The population pharmacokinetics of atovaquone were examined in 458 black, Oriental, and Malay patients with acute Plasmodium falciparum malaria receiving atovaquone alone or concomitantly with other drugs. Oral clearance (CL/F) showed a 0.674 power relationship with weight and is similar in Oriental and Malay subjects but 58.5% lower in black subjects. On the basis of mean body weight, the population estimate of CL/F is 3.28, 8.49, and 9.13 L/hr in black, Oriental, and Malay subjects, respectively. The relationship between apparent volume of distribution (V area/F) and weight was linear and similar in all three races at 7.98 L/kg. The population estimate of V area/F is 345, 383, and 428 L in black, Oriental, and Malay subjects, respectively. The bioavailability of the high and low doses of atovaquone was similar. Neither CL/F nor V area/F were significantly affected by age, gender, and the coadministration with chloroguanide (proguanil), pyrimethamine, and tetracycline. Half-life (t1/2) showed a 0.326 power relationship with weight; thus, the population estimate of t1/2 in black, Oriental, and Malay subjects is 72.9, 31.3, and 32.5 hours, respectively. The final magnitudes of interpatient variability in CL/F and V area/F were 68% and 49%, respectively.

Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis.

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Pharmacokinetics of the nitric oxide synthase inhibitor L-NG-methylarginine hydrochloride in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group.

OBJECTIVES: To characterize the pharmacokinetics of L-NG-methylarginine in patients with septic shock. METHODS: This was an international, uncontrolled, open-label study of L-NG-methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-NG-methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosing regimens were administered sequentially to separate groups of patients. RESULTS: Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first 1/2 to 4 hours. Median clearance of L-NG-methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosing cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosing cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosing cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosing cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosing cohorts, averaging 0.66 to 0.82 L/kg. CONCLUSIONS: The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-NG-methylarginine, accounting for at least 80% of clearance, is becoming progressively saturable in association with L-NG-methylarginine infusion rates > or = 5 mg/kg/h. Therefore the use of L-NG-methylarginine infusion rates > or = 5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-NG-methylarginine or both may need to be reduced accordingly.