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1.
Indian J Crit Care Med ; 24(10): 899-900, 2020 Oct.
Article En | MEDLINE | ID: mdl-33281310

How to cite this article: Peter JV. Approach to the Control of Antimicrobial Resistance: Are We Missing the Plot? Indian J Crit Care Med 2020;24(10):899-900.

2.
Indian J Med Microbiol ; 36(3): 344-351, 2018.
Article En | MEDLINE | ID: mdl-30429385

BACKGROUND: Pseudomonas aeruginosa is one of the most common opportunistic pathogens that cause severe infections in humans. The burden of carbapenem resistance is particularly high and is on the rise. Very little information is available on the molecular mechanisms and its clonal types of carbapenem-resistant P. aeruginosa seen in Indian hospitals. This study was undertaken to monitor the ß-lactamase profile and to investigate the genetic relatedness of the carbapenemase-producing (CP) P. aeruginosa collected across different hospitals from India. MATERIALS AND METHODS: A total of 507 non-duplicate, carbapenem-resistant P. aeruginosa isolated from various clinical specimens collected during 2014-2017 across seven Indian hospitals were included. Conventional multiplex polymerase chain reaction for the genes encoding beta-lactamases such as extended-spectrum beta-lactamase (ESBL) and carbapenemase were screened. A subset of isolates (n = 133) of CP P. aeruginosa were genotyped by multilocus sequence typing (MLST) scheme. RESULTS: Of the total 507 isolates, 15%, 40% and 20% were positive for genes encoding ESBLs, carbapenemases and ESBLs + carbapenemases, respectively, whilst 25% were negative for the ß-lactamases screened. Amongst the ESBL genes, blaVEB is the most predominant, followed by blaPER and blaTEM, whilst blaVIM and blaNDM were the most predominant carbapenemases seen. However, regional differences were noted in the ß-lactamases profile across the study sites. Genotyping by MLST revealed 54 different sequence types (STs). The most common are ST357, ST235, ST233 and ST244. Six clonal complexes were found (CC357, CC235, CC244, CC1047, CC664 and CC308). About 24% of total STs are of novel types and these were found to emerge from the high-risk clones. CONCLUSION: This is the first large study from India to report the baseline data on the molecular resistance mechanisms and its association with genetic relatedness of CP P. aeruginosa circulating in Indian hospitals. blaVIM- and blaNDM-producing P. aeruginosa is the most prevalent carbapenemase seen in India. Majority of the isolates belongs to the high-risk international clones ST235, ST357 and ST664 which is a concern.


Bacterial Proteins/genetics , Genotype , Molecular Epidemiology , Pseudomonas Infections/epidemiology , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/classification , Pseudomonas aeruginosa/enzymology , beta-Lactamases/genetics , Bacterial Proteins/analysis , Cross Infection/epidemiology , Cross Infection/microbiology , Genetic Variation , Humans , India/epidemiology , Multilocus Sequence Typing , Multiplex Polymerase Chain Reaction , Prevalence , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/isolation & purification , beta-Lactamases/analysis
3.
Indian J Crit Care Med ; 21(12): 811-818, 2017 Dec.
Article En | MEDLINE | ID: mdl-29307960

BACKGROUND AND AIMS: Infections in tropics often present as undifferentiated fevers with organ failures. We conducted this nationwide study to identify the prevalence, profile, resource utilization, and outcome of tropical fevers in Indian Intensive Care Units (ICUs). MATERIALS AND METHODS: This was a multicenter prospective observational study done in 34 ICUs across India (July 2013-September 2014). Critically ill adults and children with nonlocalizing fever >48 h and onset < 14 days with any of the following: thrombocytopenia/rash, respiratory distress, renal failure, encephalopathy, jaundice, or multiorgan failure were enrolled consecutively. RESULTS: Of 456 cases enrolled, 173 were children <12 years. More than half of the participants (58.7%) presented in postmonsoon months (August-October). Thrombocytopenia/rash was the most common presentation (60%) followed by respiratory distress (46%), encephalopathy (28.5%), renal failure (23.5%), jaundice (20%), and multiorgan failure (19%). An etiology could be established in 365 (80.5%) cases. Dengue (n = 105.23%) was the most common followed by scrub typhus (n = 83.18%), encephalitis/meningitis (n = 44.9.6%), malaria (n = 37.8%), and bacterial sepsis (n = 32.7%). Nearly, half (35% invasive; 12% noninvasive) received mechanical ventilation, a quarter (23.4%) required vasoactive therapy in first 24 h and 9% received renal replacement therapy. Median (interquartile range) ICU and hospital length of stay were 4 (3-7) and 7 (5-11.3) days. At 28 days, 76.2% survived without disability, 4.4% had some disability, and 18.4% died. Mortality was higher (27% vs. 15%) in patients with undiagnosed etiology (P < 0.01). On multivariate analysis, multiorgan dysfunction syndrome at admission (odds ratio [95% confidence interval]-2.8 [1.8-6.6]), day 1 Sequential Organ Failure Assessment score (1.2 [1.0-1.3]), and the need for invasive ventilation (8.3 [3.4-20]) were the only independent predictors of unfavorable outcome. CONCLUSIONS: Dengue, scrub typhus, encephalitis, and malaria are the major tropical fevers in Indian ICUs. The data support a syndromic approach, point of care tests, and empiric antimicrobial therapy recommended by Indian Society of Critical Care Medicine in 2014.

4.
Clin Toxicol (Phila) ; 52(8): 897-900, 2014.
Article En | MEDLINE | ID: mdl-25116418

BACKGROUND: Toxin-induced methemoglobinemia is seen in poisoning with oxidizing agents. We report the clinical features and outcome of patients admitted with severe methemoglobinemia due to intentional ingestion of toxicants. METHODS: In this observational case series, patients admitted with toxin-induced methemoglobinemia between September 2011 and January 2014 were identified from the institutional poisoning database. Clinical profile and outcome of patients with methemoglobin concentration greater than or equal to 49% is reported. RESULTS: Of the 824 patients admitted with poisoning, 5 patients with methemoglobin concentration greater than or equal to 49% were included. The implicated compounds were nitrobenzene, benzoylphenylurea, flubendamide and Rishab(TM). One patient refused to name the compound. All patients were managed in the intensive care unit. Altered sensorium [Glasgow coma scale (GCS) < 10] was common (80%); 2 patients presented with a GCS greater than 4. All patients manifested cyanosis, low oxygen saturation and chocolate-brown-colored blood despite supplemental oxygen therapy. The median methemoglobin concentration was 64.7% (range 49.8-91.6%); 2 patients had methemoglobin concentration greater than 70%. One patient needed inotropes. Four patients required mechanical ventilation for 4-14 days. All patients were treated with methylene blue; 4 received more than one dose. Three patients also received intravenous ascorbic acid 500 mg, once daily, for 3 days. Following treatment, there was evidence of haemolysis in all patients; 2 required blood transfusion. All patients survived. CONCLUSION: Patients with severe toxin-induced methemoglobinemia present with altered sensorium and cyanosis and may require ventilatory support and inotropes. Though methemoglobin concentrations greater than 70% are considered fatal, aggressive management with methylene blue and supportive therapy can lead to survival.


Methemoglobinemia/diagnosis , Poisons/toxicity , Administration, Oral , Adult , Cyanosis/chemically induced , Cyanosis/diagnosis , Cyanosis/drug therapy , Humans , Methemoglobin/metabolism , Methemoglobinemia/chemically induced , Methemoglobinemia/drug therapy , Methylene Blue/therapeutic use , Middle Aged , Nitrobenzenes/toxicity , Young Adult
5.
Clin Toxicol (Phila) ; 52(5): 538-41, 2014 Jun.
Article En | MEDLINE | ID: mdl-24779865

BACKGROUND: Organophosphate (OP) poisoning results in significant toxicity while pyrethroid poisoning is associated with extremely low fatality. OPs can inhibit the detoxification of pyrethroid and increase the toxicity of the combination. We assessed whether mixed OP-pyrethroid poisoning impacted outcome in human poisoning. METHODS: Patients were identified from a prospectively collected institutional poisoning database that incorporates demographic and outcome data of patients presenting with poisoning. RESULTS: Of the 1177 poisoned patients admitted over 2 years, 32 presented with OP-pyrethroid (50% chlorpyrifos-5% cypermethrin mixture) poisoning (Group 1), 26 consumed 20% chlorpyrifos (Group 2), and 32 took 15% cypermethrin (Group 3). Seizures occurred in 15.6% (n = 5) with chlorpyrifos-cypermethrin poisoning, 18.8% (n = 6) with cypermethrin poisoning, and 3.9% (n = 1) with chlorpyrifos poisoning. Ventilatory requirements were 53.5% (17/32), 42.3% (11/26), and 15.7% (5/32) in Groups 1-3, respectively. Ventilator-free days (Mean ± SD) was significantly lower (p < 0.006) in Group 1 (20.9 ± 9.3 days) than those in Group 2 (26.1 ± 4.4 days) or 3 (27.8 ± 0.6). The median (inter-quartile range) hospital stay was 5.5 (4-19.5), 5 (5-6), and 1 (0.65-1.5) days, respectively, in the three groups. Four patients died in Group 1 (13%). None died in the other groups. CONCLUSION: Although confounded by the varying quantity of chlorpyrifos and cypermethrin in the different formulations, patients with mixed poisoning appear to have shorter ventilator-free days than patients poisoned by either of the pesticides alone. Further studies are required comparing patients poisoned by formulations with similar quantities of OP and pyrethroid or with analysis of blood pesticide concentration on admission.


Chlorpyrifos/toxicity , Organophosphate Poisoning/physiopathology , Pesticides/poisoning , Pyrethrins/poisoning , Respiration, Artificial/statistics & numerical data , Adolescent , Adult , Chlorpyrifos/chemistry , Female , Hospitalization/statistics & numerical data , Humans , Length of Stay , Male , Pesticides/chemistry , Prospective Studies , Pyrethrins/chemistry , Seizures/chemically induced , Seizures/epidemiology , Young Adult
6.
Indian J Crit Care Med ; 18(2): 62-9, 2014 Feb.
Article En | MEDLINE | ID: mdl-24678147

Tropical fevers were defined as infections that are prevalent in, or are unique to tropical and subtropical regions. Some of these occur throughout the year and some especially in rainy and post-rainy season. Concerned about high prevalence and morbidity and mortality caused by these infections, and overlapping clinical presentations, difficulties in arriving at specific diagnoses and need for early empiric treatment, Indian Society of Critical Care Medicine (ISCCM) constituted an expert committee to develop a consensus statement and guidelines for management of these diseases in the emergency and critical care. The committee decided to focus on most common infections on the basis of available epidemiologic data from India and overall experience of the group. These included dengue hemorrhagic fever, rickettsial infections/scrub typhus, malaria (usually falciparum), typhoid, and leptospira bacterial sepsis and common viral infections like influenza. The committee recommends a 'syndromic approach' to diagnosis and treatment of critical tropical infections and has identified five major clinical syndromes: undifferentiated fever, fever with rash / thrombocytopenia, fever with acute respiratory distress syndrome (ARDS), fever with encephalopathy and fever with multi organ dysfunction syndrome. Evidence based algorithms are presented to guide critical care specialists to choose reliable rapid diagnostic modalities and early empiric therapy based on clinical syndromes.

7.
Clin Toxicol (Phila) ; 51(9): 850-4, 2013 Nov.
Article En | MEDLINE | ID: mdl-24066733

INTRODUCTION: Clinical scoring systems are used to predict mortality rate in hospitalized patients. Their utility in organophosphate (OP) poisoning has not been well studied. METHODS: In this retrospective study of 396 patients, we evaluated the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the Simplified Acute Physiology Score (SAPS) II, Mortality Prediction Model (MPM) II, and the Poisoning Severity Score (PSS). Demographic, laboratory, and survival data were recorded. Receiver operating characteristic (ROC) curves were generated, and the area under the curve (AUC) was calculated to study the relationship between individual scores and mortality rate. RESULTS: The mean (standard deviation) age of the patients was 31.4 (12.7) years, and at admission, their pseudocholinesterase (median, interquartile) level was 317 (222-635) U/L. Mechanical ventilation was required in 65.7% of the patients and the overall mortality rate was 13.1%. The mean (95% confidence interval) scores were as follows: APACHE-II score, 16.4 (15.5-17.3); SAPS-II, 34.4 (32.5-36.2); MPM-II score, 28.6 (25.7-31.5); and PSS, 2.4 (2.3-2.5). Overall, the AUC for mortality was significantly higher for APACHE-II (0.77) and SAPS-II (0.77) than the PSS (0.67). When patients were categorized, the AUCs were better for WHO Class II (0.71-0.82) than that for Class I compounds (0.60-0.66). For individual compounds, the AUC for APACHE-II was highest in quinalphos (0.93, n = 46) and chlorpyrifos (0.86, n = 38) and lowest in monocrotophos (0.60, n = 63). AUCs for SAPS-II and MPM-II were marginally but not significantly lower than those for APACHE-II. The PSS was generally a poorer discriminator compared to the other scoring systems across all categories. CONCLUSIONS: In acute OP poisoning, the generic scoring systems APACHE-II and SAPS-II outperform the PSS. These tools may be used to predict the mortality rate in OP poisoning.


Health Status Indicators , Insecticides/toxicity , Organophosphate Poisoning/physiopathology , APACHE , Adult , Chlorpyrifos/toxicity , Cholinesterase Inhibitors/toxicity , Cohort Studies , Hospitals, Religious , Hospitals, University , Humans , India , Medical Records , Monocrotophos/toxicity , Organophosphate Poisoning/diagnosis , Organophosphate Poisoning/mortality , Organophosphate Poisoning/therapy , Organothiophosphorus Compounds/toxicity , Prognosis , ROC Curve , Retrospective Studies , Severity of Illness Index , Young Adult
8.
Clin Microbiol Infect ; 17(9): 1355-8, 2011 Sep.
Article En | MEDLINE | ID: mdl-21679373

Influenza virus is prone to mutations that may alter the intensity of subsequent waves of infection. In this study, we evaluated whether outcomes were different in the two waves of the influenza A (H1N1) 2009 pandemic in patients admitted to the intensive-care unit. Age, gender, lag-time to presentation and APACHE-II scores were similar in both waves. Although ventilatory requirements were similar (36/37 vs. 36/39), non-significant reductions in the durations (days) of ventilation (10.3 ± 8.0 vs. 7.8 ± 9.4, p 0.11) and hospitalization (14.9 ± 10.5 vs. 12.3 ± 14.1, p 0.20) were observed in the second wave. The clinical profile and outcomes were not significantly different between the two waves among severely ill patients.


Influenza A Virus, H1N1 Subtype , Influenza, Human/epidemiology , Influenza, Human/virology , Pandemics , Adult , Cohort Studies , Female , Humans , India/epidemiology , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Risk Factors
10.
Anaesth Intensive Care ; 37(6): 944-52, 2009 Nov.
Article En | MEDLINE | ID: mdl-20014601

The aim of this study was to determine whether creatinine clearance can be estimated as well by clearance of gentamicin/tobramycin as by routine, non-invasive estimates in the intensive care unit. The volume of distribution and clearance values for gentamicin/tobramycin were obtained using first order kinetics and an estimate of creatinine clearance derived. Seven estimates of renal function (Cockroft-Gault, MDRD4 and MDRD6 equations, two- and 24-hour urine estimates, two equations utilising Cystatin C concentrations) were compared to the gentamicin/tobramycin clearance estimate in 100 intensive care unit patients. The gentamicin clearance estimate was at least as reliable as other estimates. The two-hour was less reliable than the 24-hour urine estimate. The Cockroft-Gault appeared to out-perform the MDRD equation estimates. The MDRD4 was not as reliable as the MDRD6 estimate. Cystatin C estimates appeared not as reliable as the gentamicin estimate of renal function. The gentamicin/tobramycin estimate is at least as good as other estimates and it is available sooner than most others. It should be used in all patients who are prescribed gentamicin. The two-hour urine and MDRD4 estimates should not be used in the intensive care unit.


Anti-Bacterial Agents/pharmacokinetics , Gentamicins/pharmacokinetics , Tobramycin/pharmacokinetics , Adult , Aged , Aged, 80 and over , Creatinine/blood , Creatinine/urine , Cystatin C/blood , Dose-Response Relationship, Drug , Female , Glomerular Filtration Rate , Humans , Intensive Care Units , Male , Middle Aged , Tissue Distribution , Young Adult
11.
Anaesth Intensive Care ; 36(3): 339-50, 2008 May.
Article En | MEDLINE | ID: mdl-18564794

Organophosphate poisoning is common in developing countries. The morbidity and mortality with organophosphate poisoning is relatively high despite the use of atropine as specific antidotal therapy and oximes to reactivate acetylcholinesterase. Several adjunct and alternative therapies have been explored in animal and human studies. We reviewed the literature to ascertain if there was evidence of benefit of such therapies. Adjunct and alternative therapies included treatments to reduce poison absorption by topical application of creams, enhance toxin elimination by haemoperfusion or bioremediation and neutralise the poison by scavenging free organophosphate with cholinesterase-rich human plasma. In addition, magnesium, clonidine, diazepam, N-acetyl cysteine and adenosine receptor agonists have also been used to counteract poison effects. Detailed assessment was limited by the paucity of trials on adjunct/alternative therapies. The limited evidence from the review process suggested potential benefit from the use of human plasma infusion, early initiation of haemoperfusion and intravenous magnesium, in addition to standard therapy with atropine and pralidoxime. There appeared to be no additional benefit with alkalinisation or use of glycopyrrolate instead of atropine in human trials. Diazepam administration has been advocated by military authorities if symptoms developed following exposure to organophosphate. Bioremediation, clonidine, N-acetyl cysteine and adenosine receptor agonists have been evaluated only in animal models. The impact of adjunct and alternate therapies on outcomes in human poisoning needs to be further explored before implementation as standard treatment.


Antidotes/therapeutic use , Organophosphate Poisoning , Oximes/therapeutic use , Poisoning/drug therapy , Animals , Cholinergic Antagonists/therapeutic use , Cholinesterase Reactivators/therapeutic use , Humans , Organophosphorus Compounds/antagonists & inhibitors , Organophosphorus Compounds/pharmacokinetics
13.
Drug Metab Dispos ; 33(7): 1056-61, 2005 Jul.
Article En | MEDLINE | ID: mdl-15843487

Vaccination against nicotine is being studied as a potential treatment for nicotine dependence. Some of the limitations of vaccination, such as variability in antibody titer and affinity, might be overcome by instead using passive immunization with nicotine-specific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with K(d) values ranging from 60 to 250 nM and a high-affinity polyclonal rabbit antiserum (K(d) = 1.6 nM). Pretreatment with NICmAbs substantially increased the binding of nicotine in serum after a single nicotine dose, reduced the unbound nicotine concentration in serum, and reduced the distribution of nicotine to brain. Efficacy was directly related to antibody affinity for nicotine. Efficacy of the highest affinity NICmAb, NICmAb311, was dose-related, with the highest dose reducing nicotine distribution to brain by 78%. NICmAb311 decreased nicotine clearance by 90% and prolonged the terminal half-life of nicotine by 120%. At equivalent doses, NICmAb311 was less effective than the higher affinity rabbit antiserum but comparable efficacy could be achieved by increasing the NICmAb311 dose. These data suggest that passive immunization with nicotine-specific monoclonal antibodies substantially alters nicotine pharmacokinetics in a manner similar to that previously reported for vaccination against nicotine. Antibody efficacy is a function of both dose and affinity for nicotine.


Antibodies, Monoclonal/immunology , Brain/metabolism , Nicotine/immunology , Animals , Antibody Affinity , Enzyme-Linked Immunosorbent Assay , Mice , Nicotine/pharmacokinetics , Rabbits , Rats
14.
Eur J Hum Genet ; 11(12): 945-50, 2003 Dec.
Article En | MEDLINE | ID: mdl-14508509

We earlier found an association between anorexia nervosa (AN) restrictive subtype (AN-R) and an inserted sequence within the NETpPR, a polymorphic region located in the promoter of the solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 (SLC6A2) gene. To further examine the noradrenergic system in AN-R we performed an association study with a functional polymorphism (MAOA-uVNTR) in the promoter of the monoamine oxidase A (MAOA) gene. Since monoamine oxidase A metabolises noradrenalin, a positive association with the MAOA gene would be biologically plausible. The transmission disequilibrium test and 95 trios/duos (AN-R females+biological parents) showed the main effect of the longer, more transcriptionally active form of the MAOA-uVNTR (MAOA-L) to be statistically non-significant (McNemar's chi(2)=1.4, df=1, P=0.238, odds ratio: 1.4, 95% CI 0.8-2.7). A case-control approach supported this finding. We then stratified the MAOA-uVNTR TDT data according to the (a) NETpPR genotype of the AN-R females, and (b) NETpPR allele transmitted from NETpPR-S4/L4 heterozygous mothers. In both cases, contingency table analysis revealed previously unreported gene-gene interaction between the MAOA and SLC6A2 genes (P=0.019 and 0.019, respectively). Receiving an MAOA-L allele more than doubles the risk for developing AN-R, conditional on an individual also being a NETpPR-L4 homozygote (stratum-specific odds ratio: 2.4, 95% CI 1.1-6.0). These results suggest important involvement of the noradrenergic system in the biological underpinnings of AN-R.


Anorexia Nervosa/genetics , Monoamine Oxidase/genetics , Symporters/genetics , Female , Humans , Norepinephrine Plasma Membrane Transport Proteins
15.
Int J Eat Disord ; 32(1): 24-38, 2002 Jul.
Article En | MEDLINE | ID: mdl-12183943

OBJECTIVE: The Anorexia Nervosa Stages of Change Questionnaire (ANSOCQ) was developed to assess patients' readiness to recover from anorexia nervosa. In this article we present additional findings supporting the psychometric properties of the ANSOCQ. METHOD: Forty-four inpatients with anorexia nervosa participated in the study. At the time of admission, patients were requested to complete the ANSOCQ as well as several other self-report questionnaires assessing constructs related to readiness to change. RESULTS: The ANSOCQ demonstrated good construct-related validity in that significant correlations emerged between the ANSOCQ and instruments assessing the theoretically related constructs of decisional balance and self-efficacy. DISCUSSION: Having developed a reliable and valid self-report questionnaire for the assessment of readiness to change in anorexia nervosa, the ANSOCQ provides a means of addressing motivational hypotheses which have been advanced in the context of eating disorders.


Anorexia Nervosa/diagnosis , Surveys and Questionnaires , Adaptation, Psychological , Adolescent , Adult , Anorexia Nervosa/rehabilitation , Decision Making , Female , Hospitalization , Humans , Male , Motivation , Psychometrics/statistics & numerical data , Self Efficacy , Self-Assessment , Severity of Illness Index
16.
Eat Behav ; 3(2): 133-42, 2002.
Article En | MEDLINE | ID: mdl-15001010

The paper addresses the absence of reports about the sauna use among the weight loss strategies of patients with anorexia nervosa (AN). Because AN entails a relentless pursuit of thinness, it might be expected that these patients would frequently resort to saunas. The paper sustains that the absence of reports should not be taken to mean that sauna use is irrelevant to AN. Support for this possibility is founded in the apparent progress shown by AN patients whose treatment consisted of different strategies of heat supply, which included a protocol of sauna sessions. First recommended by W. Gull, heat-treatment may be relevant to hyperactivity, a significant clinical characteristic in AN. This treatment was developed as an extrapolation from animal research model, where a simple manipulation of ambient temperature (AT) was found to impede and reverse excessive running in food-restricted rats. Sauna use may have been unreported either because it impedes the development of the syndrome, or its benefits have been attributed to conventional treatments. The elucidation of sauna experience among AN patients may have potential implications for the role of heat in the treatment of AN.

17.
Crit Care Resusc ; 4(3): 164-9, 2002 Sep.
Article En | MEDLINE | ID: mdl-16573424
18.
Pharmacotherapy ; 21(2): 183-8, 2001 Feb.
Article En | MEDLINE | ID: mdl-11213855

STUDY OBJECTIVE: To characterize frequency of liver enzyme elevation in patients with type 2 diabetes mellitus receiving troglitazone. DESIGN: Retrospective study. SETTING: Hospital-affiliated medical center. PATIENTS: Two hundred ninety-one patients with type 2 diabetes mellitus. INTERVENTION: Data from patients with an average troglitazone exposure of 412.7 +/- 255.6 days were studied. MEASUREMENTS AND MAIN RESULTS: Enzyme elevations more than 1.5 times the upper limit of normal (ULN) occurred in 17 patients (5.8%) and more than 3-fold elevations in 6 (2.1%). The relationship among enzyme elevation events, demographic factors, duration of troglitazone exposure, frequency of monitoring, and concurrent drugs (limited to glucose and lipid-lowering agents) was assessed by multiple logistic regression. Age was an independent predictor of risk (p=0.009), and concurrent insulin therapy approached statistical significance (p=0.051) for 1.5-fold ULN elevation in liver enzymes. Age and concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were the only significant predictors of 3-fold ULN elevations (p=0.03 and p=0.04, respectively). CONCLUSION: Several factors appear to increase the risk of enzyme elevation events in patients treated with troglitazone.


Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Diabetes Mellitus, Type 2/enzymology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Liver/enzymology , Thiazoles/blood , Thiazolidinediones , Adult , Age Factors , Aged , Alanine Transaminase/drug effects , Aspartate Aminotransferases/drug effects , Chi-Square Distribution , Diabetes Mellitus, Type 2/blood , Female , Humans , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Statistics, Nonparametric , Thiazoles/pharmacology
19.
Pharmacotherapy ; 20(7): 756-70, 2000 Jul.
Article En | MEDLINE | ID: mdl-10907966

STUDY OBJECTIVE: To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies. DESIGN: Two randomized, double-blind studies compared argatroban and heparin, and one open-label, dose-escalation study further evaluated argatroban. SETTING: University teaching hospital clinical research unit. PATIENTS: Healthy men (aged 22-62 yrs). INTERVENTION: In the first study, 36 subjects received an argatroban 30-, 60-, 120-, or 240-microg/kg bolus, or a heparin 30-, 60-, 120-, or 240-U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 microg/kg/minute with or without a 250-microg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125-U/kg bolus. In the third study (open-label), nine subjects received an argatroban 250-microg/kg bolus plus an infusion of 15, 20, 30, and 40 microg/kg/minute. MEASUREMENTS AND MAIN RESULTS: When administered as a bolus dose in the first study, argatroban and heparin both produced dose-related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose-related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5-9) but typically two or fewer subjects per group receiving heparin (0-7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half-life 18-41 min) than for heparin (effect half-life 23-134 min). When argatroban was infused without a bolus, peak and effect steady-state values for ACT and aPTT generally were attained within 1-3 hours. Data from the second and third studies show that for argatroban dosages up to 40 microg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight-adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated. CONCLUSION: Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.


Anticoagulants/pharmacology , Heparin/pharmacology , Pipecolic Acids/pharmacology , Adult , Anticoagulants/adverse effects , Anticoagulants/pharmacokinetics , Arginine/analogs & derivatives , Double-Blind Method , Half-Life , Heparin/adverse effects , Heparin/pharmacokinetics , Humans , Infusions, Intravenous , Male , Partial Thromboplastin Time , Pipecolic Acids/adverse effects , Pipecolic Acids/pharmacokinetics , Sulfonamides , Whole Blood Coagulation Time
20.
Obes Res ; 8(1): 43-8, 2000 Jan.
Article En | MEDLINE | ID: mdl-10678258

OBJECTIVES: Characterize degree of weight loss with stage of diabetes and describe its effect on cardiovascular disease risk factors in obese patients with and without diabetes. RESEARCH METHODS AND PROCEDURES: Retrospective cohort analysis from patients participating in a long-term weight management protocol using diet, exercise, behavioral modification, and appetite-suppressant therapy. Patient groups, with (n = 19) and without diabetes (n = 19) were matched for age, gender, and weight before weight loss therapy. The effect of 12 months of therapy on weight, blood pressure, glycemic control, lipid profile, and medication requirements were tested. Additionally, patients were grouped or staged based upon therapy required for control of diabetes at the beginning of weight loss intervention. Analysis of covariance described relationships between diabetes disease stage and weight loss at 12 months. RESULTS: Nondiabetic patients had greater mean reduction in BMI than the diabetic group (7.98 kg/m2 vs. 4.77 kg/m2, p<0.01). A significant linear trend (p<0.001) for decreasing weight loss with stage of diabetes was observed. Blood pressure, lipid profile, and glycemia improved significantly. The average daily glyburide-equivalent dose decreased from 9.4 to 3.0 mg (p<0.01). DISCUSSION: Patients with diabetes lost less weight than similarly obese patients without diabetes. Regardless of differential weight loss between groups, cardiovascular disease risk factors improved. Hypoglycemic medication requirements decreased with weight loss therapy. A predictive relationship may exist between diabetes disease stage before weight loss therapy and future weight loss potential.


Appetite Depressants/therapeutic use , Diabetes Mellitus/therapy , Obesity/therapy , Weight Loss , Adult , Behavior Therapy , Blood Glucose/metabolism , Blood Pressure , Body Mass Index , Clinical Trials as Topic , Cohort Studies , Diet, Reducing , Exercise , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/therapeutic use , Lipids/blood , Middle Aged , Retrospective Studies , Treatment Outcome
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