The evolving value assessment of cancer therapies: Results from a modified Delphi study.

The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society).

Compensation in Neonatal Clinical Trials: A Perspective.

Well conducted clinical trials are the mainstay for generating evidence on preferred treatments. In order to adequately protect the interests of the trial participants, the Central Licensing Authority of India has formulated guidelines to determine the quantum of compensation in cases of regulatory clinical trial related injury or death. However, these guidelines do not address the nuances of trials recruiting children aged under 16 years, within which, neonates are the most vulnerable population. Thus, there is a need for addressing this lacuna in the current guidelines. This article examines the challenges in determining the quantum of compensation in neonatal clinical trials using the current formula, which is a corollary to the challenges faced by the authors in procuring clinical trial insurance for the Probiotic supplementation for Prevention of Neonatal Sepsis (ProSPoNS) trial. Further, it suggests a template for a differential formula using birthweight of infants, which is one of the many important factors impacting neonatal mortality.

Allicin ameliorates aluminium- and copper-induced cognitive dysfunction in Wistar rats: relevance to neuro-inflammation, neurotransmitters and Aß(1-42) analysis.

Alzheimer's disease (AD) is a multifactorial neurological disorder associated with neuropathological and neurobehavioral changes, like cognition and memory loss. Pathological hallmarks of AD comprise oxidative stress, formation of insoluble ß-amyloid (Aß) plaques, intracellular neurofibrillary tangles constituted by hyperphosphorylated tau protein (P-tau), neurotransmitters dysbalanced (DA, NE, 5-HT, GABA and Glutamate) and metal deposition. Chronic exposure to metals like aluminium and copper causes accumulation of Aß plaques, promotes oxidative stress, neuro-inflammation, and degeneration of cholinergic neurons results in AD-like symptoms. In the present study, rats were administered with aluminium chloride (200 mg/kg p.o) and copper sulfate (0.5 mg/kg p.o) alone and in combination for 28 days. Allicin (10 and 20 mg/kg i.p) was administered from day 7 to day 28. Spatial and recognition memory impairment analysis was performed using Morris water maze, Probe trial, and Novel Object Recognition test. Animals were sacrificed on day 29, brain tissue was isolated, and its homogenate was used for biochemical (lipid peroxidation, nitrite, and glutathione), neuro-inflammatory (IL-1ß, IL-6 and TNF- α), neurotransmitters (DA, NE, 5-HT, GABA and Glutamate), Aß(1-42) level, Al concentration estimation, and Na+/K+-ATPase activity. In the present study, aluminium chloride and copper sulfate administration increased oxidative stress, inflammatory cytokines release, imbalanced neurotransmitters' concentration, and promoted ß-amyloid accumulation and Na+/K+-ATPase activity. Treatment with allicin dose-dependently attenuated these pathological events via restoration of antioxidants, neurotransmitters concentration, and inhibiting cytokine release and ß-amyloid accumulation. Moreover, allicin exhibited the neuroprotective effect through antioxidant, anti-inflammatory, neurotransmitters restoration, attenuation of neuro-inflammation and ß-amyloid-induced neurotoxicity.

Bacosides enrichment does not improve the anti-amnesic effect of Bacopa monnieri: behavioural and biochemical evidences.

Bacopa monnieri (L.) Wettst. (BM) has been traditionally used in Ayurveda for improving memory and cognitive deficits which is also evidenced through experimental and clinical studies. The neuropharmacological properties of BM are attributed to "bacosides", a complex mixture of saponin compounds. BM extracts enriched with bacosides offers commercial advantage due to perceived higher efficacy. However, there is no scientific data to support the same. In the present study, methanolic extract of BM (BME) was compared with bacosides enriched (BME-EF) vis a vis bacosides free fraction (BME-FF). Potential antioxidant and cholinesterase inhibitory activity has been evaluated using in vitro and in vivo methods. BME showed not only the highest anti-amnesic efficacy but also antioxidant and cholinesterase inhibitory activity, followed by either BME-FF or BME-EF. Interestingly, no significant differences were found in between the groups. These findings dispel the notion that bacosides enrichment enhances anti-amnesic efficacy and also suggests the contribution of other components.

Pharmacokinetics-Based Optimization of Phototherapy in Neonates Undergoing Treatment for Hyperbilirubinemia.

Introduction: Neonatal jaundice results from combined effects of both increased production of bilirubin and decreased hepatic excretory capacity in neonates. Since its discovery, phototherapy is the most widespread treatment used in neonatal jaundice. In this work, we try to search for a relationship between exposure to phototherapy and decrease in serum bilirubin (linearity vs proportionality). Methods:The present research was non-randomized prospective study conducted in the Neonatal Intensive Care Unit (NICU), Department of Paediatrics, AIIMS, New Delhi, and the Department of Pharmacology, AIIMS, New Delhi, India. Subjects were recruited from neonates admitted in NICU AIIMS, which meets our selection criteria. Infants were given a low dose of either phototherapy continuously or phototherapy for the first six hours and a double dose of phototherapy for the next six hours. Samples were collected before the beginning of the study (0 hours) and then at six and 12 hours. Bilirubin concentration was measured using HPLC and (LC-MS/MS). Results and conclusion:The percentage of reduction during the 6-12-hour interval was compared with that during the 0-6-hour interval if all experimental conditions were kept unchanged. A relationship curve between percentage of reduction and irradiance was created based on the percentage of reduction in serum bilirubin during the 0-6-hour and 0-12-hour intervals. The present study suggests that the relationship between efficacy, as measured by percentage of reduction in serum bilirubin, and irradiance is unlikely to be linear. Collected data are insufficient to clearly distinguish between proportionality and saturation point, considering that the results may be possible with both of these hypotheses.

Oxiracetam and Zinc Ameliorates Autism-Like Symptoms in Propionic Acid Model of Rats.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by restrictive behaviour, deficit in social skills and interaction. The multifactorial etiology, complex pathophysiology and different combination of symptoms (unusual speech patterns, frequent repetition of phrases) make it difficult to treat. Thus, present study aimed to find the protective effects of oxiracetam alone and in combination with zinc on brain behavioral, biochemical, pro-inflammatory cytokines and neurotransmitters level. Rats were administered with propionic acid (250 mg/kg p.o.) for 3 days and immediately on next day treatment were given with oxiracetam (25, 50 mg/kg i.p), zinc (4 mg/kg) as well as oxiracetam (25 mg/kg i.p) in combination with zinc (4 mg/kg p.o). Behavioral parameters were performed from 22th to 28th day. On 29th day, all the animals were sacrificed by cervical dislocation and the brain was preserved for biochemical (LPO, GSH, nitrite, mitochondrial complex I, IV and cAMP), neuroinflammatory (TNF-α, IL-1ß, IL-6) and neurotransmitters (5-HT, GABA, glutamate and acetylcholine) analysis. The propionic acid administration showed memory impairment, restrictive behavior, increased proinflammatory cytokines level, biochemical and neurotransmitters alteration. However, treatment with oxiracetam alone and in combination with zinc significantly attenuated behavioral, biochemical, inflammatory cytokines and restored neurotransmitters level. The finding of present study demonstrated that oxiracetam alone and in combination with zinc afforded superior anti-autistic effect through antioxidant, anti-inflammatory and anti-excitotoxic mechanisms and could serve as attractive strategy in managing autism.

Impact of Nanoclay on the pH-Responsiveness and Biodegradable Behavior of Biopolymer-Based Nanocomposite Hydrogels.

This research work deployed free radical polymerization for the development of pH-responsive hybrid nanocomposite hydrogels (NCHs) with the formation of improved interpenetrating networks (IPN). The crosslinked biopolymeric system was composed of (chitosan (CH)/guar gum (GG)/polyol) and a nanofiller (Cloisite 30B). The study was aimed to investigate the role of Cloisite 30B as a nanofiller and linseed oil-derived polyol to induce stable interpenetrating networks in chitosan‒guar gum-based hydrogels. FT-IR analysis confirmed the formation of crosslinked networks with the formation of hydrogen bonds in the synthesized NCHs. Thermogravimetric analysis and differential scanning calorimetry revealed high thermal stability of the NCHs. The hydrolytic and soil burial degradation tests confirmed the biodegradability of the synthesized NCHs. An extraordinarily high swelling capacity in a buffer solution of pH 4.0 and 7.4 demonstrated their pH-responsive behavior. It has been demonstrated that even the minimal addition of polyol to the guar gum-based hydrogels has influenced the stability and characteristic features such as high swelling capacity owing to the formation of interpenetrating networks and the biodegradability of the hydrogels.

In vivo anti-arthritic activity of Bauhinia purpurea Linn. Bark Extract.

OBJECTIVE: Bauhinia purpurea (BP) Linn. (Caesalpiniaceae) is a plant of great medicinal importance and has been used since ancient times for treating many inflammatory conditions including arthritis. This study investigates the anti-arthritic potential of the hydroalcoholic extract from the stem bark of BP. MATERIALS AND METHODS: The anti-inflammatory and anti-arthritic activity of BP at various doses was used to evaluate its anti-inflammatory activity and anti-arthritic activity. Serum of arthritic rats was collected at day 21 for detecting serum cytokines level and to evaluate the effect of BP on its serum level. Furthermore, the safety of BP was evaluated in acute (5 days) and subacute (28 days) toxicity study in rats. RESULTS: There was a significant inhibition (P < 0.01) in paw edema at a different time scale with different doses of BP (50, 100, and 200 mg/kg). BP also demonstrated dose-dependent anti-arthritic activity on all observation days (3, 7, 14, and 21). In addition, there was also a significant decrease (P < 0.01) in oxidative stress markers, circulating pro-inflammatory cytokine (tumor necrosis factor alpha from 45.91 to 37.44, interleukin-1 (IL-1) ß from 18.24 to 16.06, and IL-6 from 69.77 to 58.44) and an increase in anti-inflammatory cytokine (IL-10 from 8.07 to 12.07) levels. BP was found to be safe with an oral LD50 value of >2 g/kg in acute toxicity study and also no toxicological effect was observed in the oral subacute toxicity study. CONCLUSION: This study demonstrates that BP bark possesses anti-arthritic activity potential and confirm its folklore use in the treatment of inflammatory conditions.

Neuro-protective effect of monomethyl fumarate on ischemia reperfusion injury in rats: Role of Nrf2/HO1 pathway in peri-infarct region.

Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90 min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40 mg/kg) was administered in two divided doses at 30 min post ischemia and 5-10 min after reperfusion. After 24 h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (p < 0.05) attenuated by MMF (20 and 40 mg/kg). MMF, 20 mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1ß in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (p < 0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex.

Comparison of three different extracts of Centella asiatica for anti-amnesic, antioxidant and anticholinergic activities: in vitro and in vivo study.

Centella asiatica (CA) has been used by Ayurvedic medical practitioners in India for almost 3000 years. The neuropharmacological properties of CA and its constituents have been studied extensively. Anti-oxidant, free radical scavenging and cholinergic modulatory activities are the reported mechanisms of action for its efficacy in memory disorders. Its medicinal values are mainly attributed to the presence of several triterpenes, namely asiatic acid, madecassic acid, asiaticoside, and madecassoside. The present study was aimed to investigate the role of these triterpenes content in CA extract on the antioxidant, cholinesterase modulation and anti-amnesic properties. The fractions of CA extract enriched for (CAE-EF) and depleted/freed of (CAE-FF) triterpenes contents were compared with methanolic extract (CAE). Both in vitro and in vivo methods for evaluation of antioxidant and anticholinergic activities were used. In vitro, free radical scavenging assays (ABTS, DPPH, NO, NORAC, and ORAC) and cholinesterase (AChE and BuChE) inhibition assays were used. For evaluation of anti-amnesic effect, scopolamine induced amnesia in rats, as the acute model of memory loss was used. Following behavioural assessments (MWM, PA, EPM), biomarkers of oxidative stress (reduced GSH, MDA and SOD activity) and cholinesterase (AChE and BuChE) status were also estimated in cerebral cortex and hippocampus of rat brain. The methanolic extract (CAE) was found to perform best among all three fractions for in vitro free radical scavenging, cholinesterase inhibition, improvement of scopolamine-induced amnesia and also in vivo antioxidant effect and cholinesterase inhibitory activities. Interestingly triterpenes free fraction (CAE-FF) showed better antioxidant activity than triterpenes enriched fraction (CAE-EF) along with comparable anti-amnesic effect. This indicates that triterpenes are not solely responsible for antioxidant activity, cholinesterase inhibitory and anti-amnesic effect of CA.

Poisoning due to household products: A ten years retrospective analysis of telephone calls to the National Poisons Information Centre, All India Institute of Medical Sciences, New Delhi, India.

Extensive use of different chemicals in various fields and their easy availability has led to an increased incidence of accidental and intentional poisoning in developing countries including India. A diverse range of household products commonly used for domestic purposes comprise pesticides, household cleaners, thermometer mercury, antiseptics, kerosene, paint thinners etc. Any of these products, if misused or mishandled can cause poisoning. In India, the National Poisons Centre (NPIC) at the All India Institute of Medical Sciences, New Delhi, provides information on management of poisoning to treating physicians. Analysis of data based on telephone calls received by the NPIC (April 2006-March 2016) has highlighted a high incidence of poisoning due to household products, followed by pharmaceuticals, agricultural pesticides and industrial chemicals. The objective of the present retrospective study was to determine the incidence of poisoning due to various household products as reported to the NPIC during the ten years period. The total number of calls received by the Centre was 16,420. There were 7114 calls (45.5%) due to household products with adults (>18yrs.) and children (<1-18yrs.) constituting 38.7% and 61.2% calls respectively. Males outnumbered females (M = 62.4%, F = 37.5%). The mode of poisoning was mainly unintentional (66.8%) followed by intentional mode (33.2%). The commonest route of exposure was oral (95.6%). Household pesticides were commonly implicated (43.7%) followed by household cleaners (21.8%), thermometer mercury (5.2%) naphthalene balls (5%), antiseptics (3%), kerosene (2%) and paint thinner (2%). Miscellaneous products comprising of camphor, silica gel, hair dye, nail polish remover, cosmetics, adhesives etc were also involved in poisoning (17.1%). The trend and pattern of poisoning varies in different parts of the country, because all calls on poisoning are not reported to the Centre. So the data as such may not be a true reflection of the scenario in India. However, the results do indicate an increasing incidence of poisoning due to household products especially in children. The probable reasons for high incidence could be careless storage, ignorance, non compliance with prescribed instructions for use and negligible parental supervision in case of children. The results of the study highlight, an urgent need to identify high risk circumstances, common toxic products involved and implementation of prevention and awareness programmes, to achieve poisons control at home.

Advances in Carbon Nanotubes-Hydrogel Hybrids in Nanomedicine for Therapeutics.

In spite of significant advancement in hydrogel technology, low mechanical strength and lack of electrical conductivity have limited their next-level biomedical applications for skeletal muscles, cardiac and neural cells. Host-guest chemistry based hybrid nanocomposites systems have gained attention as they completely overcome these pitfalls and generate bioscaffolds with tunable electrical and mechanical characteristics. In recent years, carbon nanotube (CNT)-based hybrid hydrogels have emerged as innovative candidates with diverse applications in regenerative medicines, tissue engineering, drug delivery devices, implantable devices, biosensing, and biorobotics. This article is an attempt to recapitulate the advancement in synthesis and characterization of hybrid hydrogels and provide deep insights toward their functioning and success as biomedical devices. The improved comparative performance and biocompatibility of CNT-hydrogels hybrids systems developed for targeted biomedical applications are addressed here. Recent updates toward diverse applications and limitations of CNT hybrid hydrogels is the strength of the review. This will provide a holistic approach toward understanding of CNT-based hydrogels and their applications in nanotheranostics.

Protective effect of Terminalia chebula against seizures, seizure-induced cognitive impairment and oxidative stress in experimental models of seizures in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Teminalia chebula (TC) has been traditionally used in the Ayurvedic system of medicine primarily for gastrointestinal disorders. Its fruit extract has also been used to treat epilepsy and other CNS disorders. AIM OF THE STUDY: To evaluate the effect of hydroalcoholic fruit extract of Terminalia chebula (HETC) on experimental models of seizures, seizure-induced cognitive impairment and oxidative stress in rats. MATERIALS AND METHODS: In vitro antioxidant activity of HETC was evaluated by using ABTS, NO and DPPH radical scavenging assay. For in-vivo study, seizures were induced in Wistar rats (200-225g) by pentylenetetrazole (PTZ) and maximal-electroshock. (MES). The anticonvulsant effect of the HETC (250, 500, and 1000mg/kg, orally) was evaluated in seizure models. The therapeutic and sub-therapeutic dose of valproate and phenytoin were also assayed. The potential effect of co-administration of HETC (500mg/kg) with sub-therapeutic dose of valproate and phenytoin were also evaluated in PTZ and MES seizures model respectively. Effect on cognition was assessed using elevated plus maze (EPM) and passive avoidance test (PA). The in- vivo oxidative stress parameters (malondialdehyde and glutathione) were assessed in the cerebral cortex and hippocampus part of rat brain. RESULTS: The IC50 value of HETC in in vitro antioxidant assays i.e. ABTS, DPPH and NO radical scavenging assay was found to be 2.27µg/ml, 6.04µg/ml and 4.37µg/ml respectively. In experimental study, PTZ and MES treated groups exhibited 100% seizures with increased oxidative stress (p < 0.001) and cognitive deficits (p < 0.01) as compared to control group. HETC at highest dose (1000mg/kg) showed 83.33% (5/6) protection in MES induced seizures while 66.66% (4/6) protection in PTZ induced seizures. However, HETC (1000mg/kg) and co-administration of sub-therapeutic dose of HETC with valproate and phenytoin showed complete protection. In addition, it also attenuated the seizure induced oxidative stress and cognitive impairment as indicated by significant (p < 0.01) improvement in the transfer latencies in EPM and PA as compared to PTZ and MES treated group. CONCLUSIONS: The findings suggest that HETC exhibited significant anticonvulsant activity and also potentiated the subtherapeutic dose of phenytoin and valproate indicate its usefulness as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress.

Chronic treatment with taurine after intracerebroventricular streptozotocin injection improves cognitive dysfunction in rats by modulating oxidative stress, cholinergic functions and neuroinflammation.

The present study investigated the neuroprotective effects of taurine, an essential amino acid for growth and development of central nervous system. Intracerebroventricular streptozotocin (ICV-STZ) model of cognitive impairment was used in male Wistar rats (270 ± 20 g). Morris water maze, elevated plus maze and passive avoidance paradigm were used to assess cognitive performance. Taurine (40, 60 and 120 mg/kg) was administered orally for 28 days following STZ administration on day 1. Oxidative stress parameters (malondialdehyde, glutathione, nitric oxide and superoxide dismutase) and cholinesterases (acetylcholinesterase and butyrylcholinesterase) activity were measured at end of the study in the cortex and hippocampus. Levels of TNF-α, IL-1ß, expression of rho kinase-II (ROCK-II), glycogen synthase kinase-3ß (GSK-3ß) and choline acetyltransferase (ChAT) were studied in cortex and hippocampus. STZ caused significant cognitive impairment as compared to normal control. Chronic administration of taurine attenuated STZ-induced cognitive impairment. Increased oxidative stress and increased levels of TNF-α, IL-1ß induced by STZ were also significantly attenuated by taurine. Taurine significantly (p < 0.05) decreased the STZ-induced increased expression of ROCK-II in cortex and hippocampus. Further, STZ-induced increased activity of cholinesterases was significantly (p < 0.001) mitigated by taurine. STZ decreased the expression of ChAT in hippocampus which was significantly (p < 0.05) reversed by taurine. However, GSK-3ß expression was not altered by either STZ or taurine. The present study indicates that taurine exerts a neuroprotective role against STZ-induced cognitive impairment in rats. This effect is probably mediated by modulating oxidative stress, cholinesterases, inflammatory cytokines and expression of ROCK-II. Thus, this study suggests a potential of chronic taurine administration in cognitive impairment of Alzheimer's type.

Association of Physicians of India: Position Statement on Role of Chirally Pure Molecules in Clinical Practice.

Chirally pure molecules or enantiomers are non-superimposable mirror images of each other with a chiral center (such as carbon, sulphur, nitrogen or phosphorous atom). An equimolar mixture of enantiomers forms a racemate. Chirally pure molecules (single enantiomers) are important in the field of drug discovery as the drug targets such as enzymes and receptors are enantioselective in nature. Clinical studies have demonstrated that chirally pure drugs exhibit different pharmacokinetic and metabolic profiles, reduced adverse events, improved safety profiles and similar therapeutic activity at lowered drug dosage as compared with the racemate in many therapeutic areas. However, since there is a low level of awareness on the advantages of chirally pure molecules among clinicians, pharmacists and patients in India, the Association of Physicians of India (API) developed this position statement to increase awareness on the concept of chirality and the associated advantages of using chirally pure drugs in certain therapeutic areas to maximize patient outcomes. This includes the clinical evidence associated with single enantiomers such as S-metoprolol, S-amlodipine, esomeprazole, escitalopram, levobupivacaine, cisatracurium, S-etodolac, dexketoprofen, levofloxacin in terms of efficacy and safety as compared with their racemates. In addition, the API also provides some tactical recommendations for clinicians, pharmacists, patients, regulatory body and pharmaceutical companies to increase awareness on chirally pure drugs and puts forth the need for expedited availability of chirally pure drugs in the Indian market.

Study of commonly used organophosphate pesticides that induced oxidative stress and apoptosis in peripheral blood lymphocytes of rats.

In a previous study, we have found that organophosphate (OP) pesticides such as chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) significantly induced genotoxicity in peripheral blood lymphocytes of rats. To explore the mechanism of OP-induced genotoxicity, we measured the formation of DNA interstrand cross-links (DICs) and apoptosis in peripheral blood lymphocytes of rats. Peripheral blood lymphocytes of rats were treated with CPF, MPT, and MLT individually and in combination at concentrations of 0.1 and 0.25 LC50 for 2, 4, 8, and 12 h at 37°C. Lipid peroxidation (LPO) was measured as a biomarker of oxidative stress. Apoptosis induced by CPF, MPT, and MLT individually and in combination was determined by measuring the intracellular level of active caspase-3 and caspase-9 by spectrofluorimetry. We found significant dose- and time-dependent increases in LPO, DICs formation and increase of intracellular active caspase-3 and caspase-9 in exposed peripheral blood lymphocytes of rats. These findings suggest that the studied pesticides have potential to induce oxidative stress, cause DNA adduct formation, and cause failure of adduct repair, which leads to apoptosis that is partially mediated by activation of intracellular caspase-3 and caspase-9.

Rifampicin and anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic interactions and their clinical impact.

Patients on dialysis have an increased incidence of tuberculosis (TB). Rifampicin, a first-line antitubercular therapy (ATT) drug, is a potent inducer of hepatic cytochrome P450 (CYP). There is potential for pharmacokinetic interaction between rifampicin and anti-hypertensives that are CYP substrates: amlodipine and metoprolol. Therefore, hypertensive patients receiving rifampicin-based ATT are at risk for worsening of hypertension. However, this hypothesis has not yet been systematically studied. In this prospective study, hypertensive CKD 5D patients with TB were followed after rifampicin initiation. Blood pressure (BP) was ≤140/90 mmHg with stable anti-HT requirement at inclusion. Serum amlodipine, metoprolol, and prazosin levels were estimated by high-performance liquid chromatography at baseline and 3, 7, 10, and 14 days after rifampicin initiation. BP and anti-HT requirement were monitored for 2 weeks or until stabilization. All 24 patients in the study had worsening of hypertension after rifampicin and 83.3% required increase in drugs to maintain BP <140/90 mmHg. Serial amlodipine levels were estimated in 16 patients; metoprolol and prazosin in four patients each. Drug levels declined by >50% in all patients and became undetectable in 50-75%. Drug requirement increased from 4.5 ± 3.6 to 8.5 ± 6.4 units (P < 0.0001). Mean time to first increase in dose was 6.5 ± 3.6 days. Eleven (46%) patients experienced a hypertensive crisis at 9.1 ± 3.8 days. Three of them had a hypertensive emergency with acute pulmonary edema. In two patients, rifampicin had to be discontinued to achieve BP control. In conclusion, rifampicin caused a significant decrease in blood levels of commonly used anti hypertensives. This decrease in levels correlated well with worsening of hypertension. Thus, we suggest very close BP monitoring in CKD patients after rifampicin initiation.