Nitin Mali | Seth G S Medical College/Kem Hospital (original) (raw)
Papers by Nitin Mali
The International Journal of Tuberculosis and Lung Disease, 2019
To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. M E T H ... more To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. M E T H O D S : INH levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1-15 years on daily anti-tuberculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after INH administration. The maximum concentration (C max) and area under the curve (AUC 0-24) were determined. The normal therapeutic range for C max is 3-5 lg/ml. An AUC of ,10.52 lg h/ml for INH is low. R E S U LT S : The mean C max was 8.3 6 4.28 lg/ml and was attained in 1.22 6 0.5 h, with a median time to C max (T max) of 1 h. The mean AUC for INH was 46.23 6 34.82 lg h/ml. Children aged 1-4.9 years, 5-10 years and .10 years had a mean C max of respectively 9.87 6 5.75 lg/ml, 7.62 6 3.37 lg/ml and 7.21 6 2.50 lg/ml
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine, 2019
Aims and objectives Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infe... more Aims and objectives Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infections and is largely prescribed to pediatric intensive care unit (PICU) patients. Despite the different pathophysiology of these patients, limited data are available on pharmacokinetics of vancomycin. There are lack of data for critically ill Indian children; hence, study was conducted to assess the steady-state pharmacokinetics in children admitted to PICU. Materials and methods Twelve subjects (seven males, five females) aged 1–12 years were enrolled. Vancomycin (dose of 20 mg/kg per 8 hours) was infused for over 1 hour and steady-state pharmacokinetics was performed on day 3. Vancomycin concentrations were measured by the validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). Results The steady-state mean Cssmax was 40.94 μg/mL (±15.07), and mean AUC0–8 hours was 124.15 μg/mL (±51.2...
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine, 2019
Rationale Vancomycin remains the standard of care for gram-positive bacterial infections, though ... more Rationale Vancomycin remains the standard of care for gram-positive bacterial infections, though there are significant developments in newer antibacterial agents. Efficacy can be improved by linking pharmacokinetic with pharmacodynamic principles, thus leading to optimum antibiotic exposure. There is scarcity of pharmacokinetic data in Indian intensive care unit (ICU) population. Materials and methods Fifteen subjects with suspected or proven gram-positive bacterial infection of either gender between 18 years and 65 years of age were enrolled. Vancomycin at the dose of 1 g every 12 hours was administered over 1-hour period and pharmacokinetic assessments performed on blood samples collected on days 1 and 3. Vancomycin concentrations were measured on validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). Results The mean Cmax, elimination half-life, AUC0–12hours, volume of distribut...
European Journal of Drug Metabolism and Pharmacokinetics
An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling micr... more An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats. ATIS-diazepam (1 mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC–MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy. ATIS-diazepam exhibited globule size < 200 nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10 min, which was sustained over 1 h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution. Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.
Indian Journal of Critical Care Medicine
Patients admitted to the medical intensive care unit (MICU) of tertiary referral centers are crit... more Patients admitted to the medical intensive care unit (MICU) of tertiary referral centers are critically ill and incidences of nosocomial infections are also very high. [1,2] Antibacterial agents are the most prescribed drugs for rapid control of serious infections to reduce the mortality and morbidity. [2-4] The burden of bacterial disease in India is among highest in the world and the inappropriate use of antibacterial agents leads to increase the development of antibacterial resistance. [1,5,6] Antibiotic resistance has been a low-priority area in most developing and many developed countries. To overcome the burden of infectious disease and rising antibiotic resistance prevalence in India, the Global Antibiotic Resistance Partnership-India Working Group have recommended important interventions which include surveillance of antibiotic use, distributing standard treatment guidelines, increasing the use of diagnostics tests, infection control interventions, educational approaches, and improving antibiotic supply chain and quality. [5] A drug utilization study is a potential tool which not only assesses the current prescribing pattern of drugs but also assess the disease burden as well resistance pattern of microorganisms and recommends necessary interventions to be used to achieve rational prescribing practice. [7] Resistance to important antibacterials such as vancomycin and colistin are increasing globally. [8,9] Majority of antibacterial
Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine, 2018
Antibacterials are commonly prescribed to Pediatric Intensive Care Unit (PICU) patients. However,... more Antibacterials are commonly prescribed to Pediatric Intensive Care Unit (PICU) patients. However, inappropriate antibacterial prescriptions lead to increases in antibacterial resistance, treatment cost, duration of treatment, and poor clinical outcome. The antibacterial utilization study assesses the prescription patterns and if necessary recommends the interventions to improve antibacterial prescriptions. Hence, the present prospective groundwork was conducted. The study was conducted over the period of 6 months (April 18 to October 20, 2014). The demographics and drug use details were captured daily from patients admitted to PICU to assess World Health Organization indicators. A total of 200 patients enrolled, among them 119 males and 81 females. There were 12.46 (±6.16) drugs prescribed per patient, of which 2.38 (±1.48) were antibacterials. Among the total drug prescribed, 18.49% were antibacterials and 97% patients received at least one antibacterial. Ceftriaxone (49.48%) was t...
Journal of Ayurveda and Integrative Medicine
Background: Genetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabo... more Background: Genetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabolizing capacity and a unique phenotype to an individual. Phenytoin has large inter-individual variability in metabolism due to polymorphisms in CYP2C9 and CYP2C19. As per Ayurveda, Prakriti imparts a unique phenotype to an individual. Objective: To assess whether Prakriti can substitute phenotyping [therapeutic drug monitoring (TDM)] and genotyping in individualizing therapy with phenytoin in epilepsy patients. Methods and materials: This was a cross-sectional study conducted over a period of three years. Prakriti was assessed using standardized and validated software. Polymorphisms in CYP2C9 and CYP2C19 were assessed using Polymerase Chain Reaction (PCR)-Restriction fragment length polymorphism (PCR-RFLP). Plasma concentrations of phenytoin (phenotype) were determined using reverse phase-high performance liquid chromatography (RF-HPLC). Results: Total 351 patients were enrolled for the study. Kapha vata (KV) (39%) was the predominantly observed Prakriti followed by vata kapha (VK) (20.8%) and vata pitta (VP) (8.83%) among the patients. The CYP2C9 and CYP2C19 genotype distributions were in accordance with HardyeWeinberg equilibrium. There was no association between Prakriti and genotypes and Prakriti and phenotype (p > 0.05 each). Patients with CYP2C9 *1/*3 genotype were thrice more likely to have toxic plasma concentrations of phenytoin as compared to those with wild-type genotype (*1/*1) (Adjusted odds ratio e 3.36; 95% C.I. 1.61, 7.01). However, no such association was observed between polymorphisms of CYP2C19 and phenotype. Conclusions: We did not find any association between Prakriti and either phenotype or genotypes suggesting that Prakriti assessment would be of limited utility in individualizing phenytoin therapy in epilepsy patients.
Indian Journal of Pharmacology, 2014
Cytochrome P450 2D6 (CYP2D6) metabolizes around 25% of the drugs used in therapeutics and differe... more Cytochrome P450 2D6 (CYP2D6) metabolizes around 25% of the drugs used in therapeutics and different polymorphisms have been identified in various populations. This study aimed at finding the prevalence of CYP2D6 polymorphisms using dextromethorphan as a probe drug. Healthy participants were administered 60 mg dextromethorphan after an overnight fast and 5 ml of blood was collected 3 h postdose. A validated laboratory method was used to measure both dextromethorphan and its active metabolite, dextrorphan from plasma. Metabolic ratio (MR) of dextromethorphan to dextrorphan was calculated for each of the participants. Probit analysis was done and antimode was defined. Individuals with log MR equal to or higher than the antimode were classified as poor metabolizers (PMs) and those with values less than antimode were categorized as extensive metabolizers (EMs). Data from a total of 149 participants were evaluated and the median (range) of MR was 0.25 (0.03-3.01). The polynomial equation obtained in probit analysis gave an antimode for MR of 1.39. Five (3.36%) participants were PMs and 144 (96.64%) were found to be EMs. One participant had reported mild drowsiness 2 h postdose that subsided spontaneously without any intervention. The prevalence of CYP2D6 polymorphism in Western Indian population is low (3.36%) and is similar to other populations.
The International Journal of Tuberculosis and Lung Disease, 2019
To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. M E T H ... more To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. M E T H O D S : INH levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1-15 years on daily anti-tuberculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after INH administration. The maximum concentration (C max) and area under the curve (AUC 0-24) were determined. The normal therapeutic range for C max is 3-5 lg/ml. An AUC of ,10.52 lg h/ml for INH is low. R E S U LT S : The mean C max was 8.3 6 4.28 lg/ml and was attained in 1.22 6 0.5 h, with a median time to C max (T max) of 1 h. The mean AUC for INH was 46.23 6 34.82 lg h/ml. Children aged 1-4.9 years, 5-10 years and .10 years had a mean C max of respectively 9.87 6 5.75 lg/ml, 7.62 6 3.37 lg/ml and 7.21 6 2.50 lg/ml
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine, 2019
Aims and objectives Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infe... more Aims and objectives Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infections and is largely prescribed to pediatric intensive care unit (PICU) patients. Despite the different pathophysiology of these patients, limited data are available on pharmacokinetics of vancomycin. There are lack of data for critically ill Indian children; hence, study was conducted to assess the steady-state pharmacokinetics in children admitted to PICU. Materials and methods Twelve subjects (seven males, five females) aged 1–12 years were enrolled. Vancomycin (dose of 20 mg/kg per 8 hours) was infused for over 1 hour and steady-state pharmacokinetics was performed on day 3. Vancomycin concentrations were measured by the validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). Results The steady-state mean Cssmax was 40.94 μg/mL (±15.07), and mean AUC0–8 hours was 124.15 μg/mL (±51.2...
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine, 2019
Rationale Vancomycin remains the standard of care for gram-positive bacterial infections, though ... more Rationale Vancomycin remains the standard of care for gram-positive bacterial infections, though there are significant developments in newer antibacterial agents. Efficacy can be improved by linking pharmacokinetic with pharmacodynamic principles, thus leading to optimum antibiotic exposure. There is scarcity of pharmacokinetic data in Indian intensive care unit (ICU) population. Materials and methods Fifteen subjects with suspected or proven gram-positive bacterial infection of either gender between 18 years and 65 years of age were enrolled. Vancomycin at the dose of 1 g every 12 hours was administered over 1-hour period and pharmacokinetic assessments performed on blood samples collected on days 1 and 3. Vancomycin concentrations were measured on validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). Results The mean Cmax, elimination half-life, AUC0–12hours, volume of distribut...
European Journal of Drug Metabolism and Pharmacokinetics
An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling micr... more An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats. ATIS-diazepam (1 mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC–MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy. ATIS-diazepam exhibited globule size < 200 nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10 min, which was sustained over 1 h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution. Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.
Indian Journal of Critical Care Medicine
Patients admitted to the medical intensive care unit (MICU) of tertiary referral centers are crit... more Patients admitted to the medical intensive care unit (MICU) of tertiary referral centers are critically ill and incidences of nosocomial infections are also very high. [1,2] Antibacterial agents are the most prescribed drugs for rapid control of serious infections to reduce the mortality and morbidity. [2-4] The burden of bacterial disease in India is among highest in the world and the inappropriate use of antibacterial agents leads to increase the development of antibacterial resistance. [1,5,6] Antibiotic resistance has been a low-priority area in most developing and many developed countries. To overcome the burden of infectious disease and rising antibiotic resistance prevalence in India, the Global Antibiotic Resistance Partnership-India Working Group have recommended important interventions which include surveillance of antibiotic use, distributing standard treatment guidelines, increasing the use of diagnostics tests, infection control interventions, educational approaches, and improving antibiotic supply chain and quality. [5] A drug utilization study is a potential tool which not only assesses the current prescribing pattern of drugs but also assess the disease burden as well resistance pattern of microorganisms and recommends necessary interventions to be used to achieve rational prescribing practice. [7] Resistance to important antibacterials such as vancomycin and colistin are increasing globally. [8,9] Majority of antibacterial
Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine, 2018
Antibacterials are commonly prescribed to Pediatric Intensive Care Unit (PICU) patients. However,... more Antibacterials are commonly prescribed to Pediatric Intensive Care Unit (PICU) patients. However, inappropriate antibacterial prescriptions lead to increases in antibacterial resistance, treatment cost, duration of treatment, and poor clinical outcome. The antibacterial utilization study assesses the prescription patterns and if necessary recommends the interventions to improve antibacterial prescriptions. Hence, the present prospective groundwork was conducted. The study was conducted over the period of 6 months (April 18 to October 20, 2014). The demographics and drug use details were captured daily from patients admitted to PICU to assess World Health Organization indicators. A total of 200 patients enrolled, among them 119 males and 81 females. There were 12.46 (±6.16) drugs prescribed per patient, of which 2.38 (±1.48) were antibacterials. Among the total drug prescribed, 18.49% were antibacterials and 97% patients received at least one antibacterial. Ceftriaxone (49.48%) was t...
Journal of Ayurveda and Integrative Medicine
Background: Genetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabo... more Background: Genetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabolizing capacity and a unique phenotype to an individual. Phenytoin has large inter-individual variability in metabolism due to polymorphisms in CYP2C9 and CYP2C19. As per Ayurveda, Prakriti imparts a unique phenotype to an individual. Objective: To assess whether Prakriti can substitute phenotyping [therapeutic drug monitoring (TDM)] and genotyping in individualizing therapy with phenytoin in epilepsy patients. Methods and materials: This was a cross-sectional study conducted over a period of three years. Prakriti was assessed using standardized and validated software. Polymorphisms in CYP2C9 and CYP2C19 were assessed using Polymerase Chain Reaction (PCR)-Restriction fragment length polymorphism (PCR-RFLP). Plasma concentrations of phenytoin (phenotype) were determined using reverse phase-high performance liquid chromatography (RF-HPLC). Results: Total 351 patients were enrolled for the study. Kapha vata (KV) (39%) was the predominantly observed Prakriti followed by vata kapha (VK) (20.8%) and vata pitta (VP) (8.83%) among the patients. The CYP2C9 and CYP2C19 genotype distributions were in accordance with HardyeWeinberg equilibrium. There was no association between Prakriti and genotypes and Prakriti and phenotype (p > 0.05 each). Patients with CYP2C9 *1/*3 genotype were thrice more likely to have toxic plasma concentrations of phenytoin as compared to those with wild-type genotype (*1/*1) (Adjusted odds ratio e 3.36; 95% C.I. 1.61, 7.01). However, no such association was observed between polymorphisms of CYP2C19 and phenotype. Conclusions: We did not find any association between Prakriti and either phenotype or genotypes suggesting that Prakriti assessment would be of limited utility in individualizing phenytoin therapy in epilepsy patients.
Indian Journal of Pharmacology, 2014
Cytochrome P450 2D6 (CYP2D6) metabolizes around 25% of the drugs used in therapeutics and differe... more Cytochrome P450 2D6 (CYP2D6) metabolizes around 25% of the drugs used in therapeutics and different polymorphisms have been identified in various populations. This study aimed at finding the prevalence of CYP2D6 polymorphisms using dextromethorphan as a probe drug. Healthy participants were administered 60 mg dextromethorphan after an overnight fast and 5 ml of blood was collected 3 h postdose. A validated laboratory method was used to measure both dextromethorphan and its active metabolite, dextrorphan from plasma. Metabolic ratio (MR) of dextromethorphan to dextrorphan was calculated for each of the participants. Probit analysis was done and antimode was defined. Individuals with log MR equal to or higher than the antimode were classified as poor metabolizers (PMs) and those with values less than antimode were categorized as extensive metabolizers (EMs). Data from a total of 149 participants were evaluated and the median (range) of MR was 0.25 (0.03-3.01). The polynomial equation obtained in probit analysis gave an antimode for MR of 1.39. Five (3.36%) participants were PMs and 144 (96.64%) were found to be EMs. One participant had reported mild drowsiness 2 h postdose that subsided spontaneously without any intervention. The prevalence of CYP2D6 polymorphism in Western Indian population is low (3.36%) and is similar to other populations.