A previous study of our group also

suggested that alterat

A previous study of our group also

suggested that alterations in early periods after birth could be involved in behavioral deficits in adulthood (Moreira et al., 2010). The exact mechanism involved in the long-term effects of KA-induced seizures on behavioral performance in adulthood is still unknown, but appears to involve impairment of the long-term potentiation, enhanced long-term depression and reduction on synaptic proteins levels (Cognato et al., 2010, Cornejo et al., 2007 and Sun et al., 2009). Apparently, astrogliosis AZD5363 order is not persistent up to adulthood in this model (Cognato et al., 2010). The early periods of brain development are of great relevance and determine adequate brain function late in lifespan. Our study indicates that a single convulsive event in early life could induce short-term alterations in relevant parameters involved in the homeostasis of glutamatergic neurotransmission in the hippocampus, which could be involved in the

behavioral alterations in adulthood animals. Our findings can contribute to better understand the role of glutamate transporters in seizures during childhood. From clinical point of view, our data suggest that interventions on the glutamatergic system during seizures in children may be relevant for prevention of brain impairment in adulthood. This work was support by CAPES, FAPERGS, INCT.EN-CNPq/INCT and IBN.Net FINEP/FADESP (Proc. No. 01.06.0842-00). Special thanks to Jocemar Ilha and Henrique Beck Biehl for the support. None of the authors has any conflict of interest to disclose. “
“Monoamine transporters RAD001 solubility dmso for serotonin (SERT), norepinephrine (NET) and dopamine (DAT) belong to the family of Na+/Cl−-dependent neurotransmitter transporters and remove their substrates to end synaptic transmission (Kristensen et al., 2011). Apart from this physiological role, these transporters

are the targets of illicit drugs like cocaine or amphetamines (Rothman and Baumann, 2003). Amphetamines lead to a reverse action of all of these transporters and to a number of other intracellular effects which first actively increase the concentration of neurotransmitters in the synaptic cleft (Sitte and Freissmuth, 2010). In contrast, cocaine raises the synaptic concentration of monoamines by inhibiting the activity of these transporters. Both classes of compounds are sold on the street market for illicit drugs at the risk of the users because both the quality and identity of the purchased drugs are without any control. This situation is alleviated by the government-supported Viennese drug prevention project ‘checkit! Check your drugs’, which offers cost-free and anonymous analyses of drugs. Thereby drug consumers gain information about the contents of their drug as well as possible risks of those compounds. Importantly and often to the great surprise of the user, the purchased drug does not contain the compound under the name it was sold.

Contrary to expectations, total therapy duration was found to be

Contrary to expectations, total therapy duration was found to be overestimated more in individual therapy sessions than in circuit class therapy sessions.

There are two main implications of these findings. First, in terms of Lonafarnib price clinical practice, accurate quantification of therapy dose is important to allow for reflection on current practice and to measure changes in practice accurately. The National Stroke Foundation Clinical Guidelines for Stroke Management (2010) recommend that stroke survivors should be provided with as much opportunity as possible to engage in active task practice during the first six months after stroke. The results of this study showed that, on average, therapists overestimated active time by 28%, and underestimated rest time by 36%. This means, that in an hour-long therapy session, therapists believe their patients are active for 17 minutes more than they actually are. Conversely, patients are resting for 22 minutes longer than estimated. This finding is in line with other studies examining therapists’ accuracy of estimating therapy time (Bagley et al 2009). These findings suggest that when accurate data for therapy dose are required, such as for research or to monitor adherence

to clinical guidelines, more objective methods of measurement should be employed. For example, simple counting of repetitions of tasks or exercises has been used to describe therapy dosage in clinical trials (Birkenmeier et al 2010), and many stroke survivors in rehabilitation are able to accurately count repetitions BGB324 order of their own practice (Scrivener et al 2011). More detailed information about physical activity both SPTLC1 in therapy and across the day can be collected using activity monitors such as accelerometers. To date, the majority of studies using activity monitors have been conducted with ambulatory, community

dwelling stroke survivors (Alzahrani et al 2011, Manns and Baldwin, 2009, Rand et al 2009). Less is known about the accuracy of these monitors to detect activity in people early after stroke who may move very slowly, and activity monitors cannot provide information about the context and purpose of activity. Second, in light of these findings, one of the reasons therapy dosage studies have shown small effect sizes may be that many have relied on therapist estimations of therapy time. It is possible that if dose of therapy were more accurately quantified in these studies, a larger effect may have been detected. This is of course speculative, but serves to highlight the need for accurate quantification of therapy dosage in clinical trials. This study has several strengths: it involved multiple rehabilitation centres, examined both individual and circuit class therapy sessions, and involved clinicians with a range of experience.

, 1999 and Whincup et al , 2002) In this paper we describe the d

, 1999 and Whincup et al., 2002). In this paper we describe the development process of a childhood obesity prevention intervention targeting primary school-aged children from this cultural group (the UK National Prevention Research Initiative-funded BEACHeS study). Specifically we reflect on the utility of a well-recognised complex intervention development framework tool (the MRC Framework; Campbell et al., 2000) as a means to ensure that contextual information is gathered and incorporated into the intervention design. This is analogous to stage find more 1 of the NIH Stage Model (Onken et al., 1997), which emphasises the importance of incorporating qualitative research methods into intervention

development. The stages outlined in the MRC Framework (Campbell et al., 2000) and also in the Stage Model (Onken et al., 1997) are akin to the sequential phases of drug development. The theoretical phase (preclinical/Stage 0) and modelling phase (phase I/Stage 1a) inform the development of behavioural interventions prior to feasibility or exploratory testing (phase II/Stage 1b), and precede the more definitive clinical trial and implementation phases (phases III–IV/Stages 2–5). In this study, the methodologies

employed were a literature review on childhood obesity prevention, focus groups (FGs) with local stakeholders, a Professionals Group meeting, and a review of existing community resources. Each of these is discussed in turn below. A further theoretical framework was used

to assist in the analysis MAPK inhibitor and application of the contextual data during the intervention development process; the Analysis Grid because for Environments Linked to Obesity (ANGELO framework; Swinburn et al., 1999). This framework guides users to categorise ‘obesogenic’ environmental influences into four types: physical, economic, political and sociocultural, and consider these categories at both local and macro-levels. Data arising from the literature review and the stakeholder FGs were mapped to this framework, which was then used to inform decisions on components to include in the final intervention programme. We systematically searched the Cochrane, MEDLINE and the NIHR Centre for Reviews and Dissemination databases for childhood obesity prevention systematic reviews and evidence-based guidelines to ensure that the developed intervention was coherent with the existing evidence. In addition, the following websites were searched: National Institute for Health and Clinical Excellence, NIHR Health Technology Assessment Programme, Scottish Intercollegiate Guidelines Network, and Swedish Council on Health Technology Assessment. Publications up to the end of 2006 were included in the review. We dissected intervention programmes reported in the literature into their component parts.

Finally, one can envision that other immunomodulatory agents coul

Finally, one can envision that other immunomodulatory agents could be incorporated into SVPs to further fine-tune the immune response by targeting specific subsets of immune cells, such as CD8 T cells, Th1 cells, Th2 cells, Tfh, Th17 cells, T regulatory cells, B cells, and NK T cells. Collectively, the

data reported here suggest an approach to utilize TLR agonists as parenterally administered vaccine adjuvants in a clinical setting while minimizing the risk of systemic adverse reactions. Co-encapsulation of antigen has the added benefit of co-delivery of adjuvant and antigen directly to APCs. The SVP approach is currently being evaluated in pre-clinical studies such as cancer and chronic infections, where traditional adjuvants are inadequate, and in a Phase 1 clinical study for smoking cessation, where high concentrations MLN0128 molecular weight of antibodies against nicotine are thought to be necessary for therapeutic efficacy. We thank Aditi Chalishazar, Ingrid Soltero and Alyssa Rague for their expert technical help. Conflict of interest: Petr Ilyinskii, Christopher Roy, Conlin O’Neil, Erica Browning, Lynnelle Pittet, David Altreuter, Lloyd Johnston, and Takashi Kei Kishimoto are employees and shareholders click here of Selecta Biosciences. Robert Langer,

Omid Farokhzad and Ulrich H. von Andrian are founders and shareholders of Selecta Biosciences. Frank Alexis, Elena Tonti, Jinjun Shi, Pamela A. Basto, Aleksandar F. Radovic-Moreno and Matteo Iannacone report no conflict of interest.

“CD4 T cells provide ‘help’ in stimulating B cells to mature as well as undergo immunoglobulin Resveratrol class switching and affinity maturation, and as a result are required for development of a successful vaccine. In order to provide help CD4 T cells must recognize HLA Class II epitopes found in the immunogen. Unfortunately not all vaccines have sufficient HLA Class II epitopes to induce a proper T cell helper response in a diverse population. As a consequence there may be some value in designing a ‘universal’ helper T cell epitope to be included in the vaccine. A limiting factor for targeting a specific CD4 response to induce T cell help in a vaccine is the large number of polymorphisms in MHC class II genes. Each individual has specific set of MHC class II alleles, and each allele may have different peptide-binding properties [1]. As a consequence, a universal CD4 T cell helper peptide would have to bind promiscuously to multiple alleles to provide broad coverage across a population. In addition, the peptide would preferably make use of pre-existing CD4 T cell memory to give a rapid and robust response. The concept of the need for a ‘promiscuous’ or universal helper peptide has been studied by a number of groups.

4) These data indicate that the inhibition of Kv-channel current

4). These data indicate that the inhibition of Kv-channel currents by (+)MK801 does not depend on the channel activation or inactivation

state. Next, we investigated the steady-state kinetics of Kv channels in the presence and absence of (+)MK801. Steady-state activation of Kv channels was measured using the conventional method by using peak tail currents at −35 mV after various test potentials (upper panel of Fig. 5A). Steady-state inactivation AT13387 ic50 kinetics were also examined using a conventional double-pulse protocol (upper panel of Fig. 5B), which is explained in detail in the Data analysis subsection of the Methods and in the Fig. legend. The results presented in Fig. 1, Fig. 3 and Fig. 4 suggested that (+)MK801 is unlikely to preferentially interact with and modulate the Kv channels in activated or inactivated states in RMASMCs.

In accord, (+)MK801 had little effect on steady-state activation and inactivation kinetics of Kv channels in RMASMCs (Fig. 5A & B). The potential at the half-activation point (V1/2) and the slope value (k) of the steady-state activation curves were −8.6 ± 0.9 and 12.8 ± 0.6 mV for controls, −12.9 ± 1.2 and 10.3 ± 0.7 mV for 100 μM (+)MK801, and −11.9 ± 1.1 and 8.0 ± 0.5 mV for 300 μM (+)MK801, respectively. Furthermore, the V1/2 and k values of the steady-state inactivation curves were −30.7 ± 0.8 and 7.5 ± 0.7 mV for controls, −34.4 ± 1.3 and 8.0 ± 0.8 mV for 100 μM (+)MK801, and −31.5 ± 1.5 and 6.6 ± 1.0 mV for 300 μM (+)MK801, respectively. The time course of the recovery JNJ-26481585 research buy Phosphatidylinositol diacylglycerol-lyase from inactivation of the Kv-channel currents in RMASMCs was also examined in the absence and presence of (+)MK801. The voltage-pulse protocol for measuring the recovery from inactivation is shown in the inset in

Fig. 6A. The recovery time courses in the absence and presence of (+)MK801 were similar: the time constants of the recovery from inactivation of Kv-channel currents in the absence and presence of (+)MK801, which were obtained by data fitting to a single exponential decay curve, were 311 ± 41 and 325 ± 58 ms, respectively. (−)MK801, an optical isomer of (+)MK801, is substantially less effective than (+)MK801 in blocking the NMDAr (9). Thus, we compared the inhibitory effects of (−)MK801 on Kv-channel currents in RMASMCs with the effects produced by (+)MK801. (−)MK801 inhibited Kv-channel currents in a concentration-dependent manner (Fig. 7A). The I–V relationships of the channel currents in the presence and absence of 300 and 1000 μM (−)MK801 are shown in Fig. 7B. Fig. 7C summarizes the concentration-dependent inhibition of Kv-channel currents by (−)MK801. A nonlinear least-squares fit of the Hill equation to the concentration–effect curve of (−)MK801 yielded an IC50 and a Hill coefficient of 134.0 ± 17.5 μM and 0.87 ± 0.09, respectively.

5 and 6 Drug interactions that result in an altered pharmacokinet

5 and 6 Drug interactions that result in an altered pharmacokinetics are mainly observed with those beta-blockers that are excreted via metabolism (Metoprolol and carvedilol). Hence, Metoprolol has a higher potential for drug interactions. Selleck Raf inhibitor Considering modulation of CYP2D6 by both of these two drugs, Duloxetine and Metoprolol, possible interaction at P-glycoprotein, this study was undertaken to evaluate the influence of Duloxetine on the pharmacokinetics of Metoprolol

in rat model. Metoprolol was obtained as a gift sample from Matrix Laboratories, Hyderabad (India). Duloxetine was obtained as a gift sample from Hetero Laboratories, Hyderabad (India). All HPLC grade solvents (acetonitrile, methanol and water) were procured from SD Fine chemicals, Mumbai, India. All other chemicals used were of analytical grade and purchased from local chemical agencies. HPLC (A Shimadzu Class VP series HPLC system) with two LC-10AT pumps, an SPD-10A variable wavelength programmable UV/Vis detector, an SCL-10A system controller was manufactured by DONG-IL Shimadzu Corporation, Kangnam-Ku, Seoul, Korea. Zodiac C8, 150 mm × 4.6 mm, 5 μm was used. The system was equipped with Class VP series version 6.12 software. Sonicator (Hwashin Technology, Seoul, Korea), Biofuge (Hearus instrument, Hanau, Germany), micropipettes,

tubes (Tarsons Products Pvt. Ltd, Kolkata, India) were used. Albino Wistar rats (National Institute of Nutrition, Hyderabad, India), of either sex, weighing 200–250 g, were selected. Animals were maintained under standard JQ1 laboratory conditions at 25 ± 2 °C, relative humidity 50 ± 15% and normal photoperiod (12 h

dark/12 h light). Commercial pellet diet (Rayon’s Biotechnology Pvt. Ltd, India) and water were provided ad libitum. The experimental protocol was approved by the Institutional Animal Ethics Committee of AMR Memorial College of Pharmacy on 04-05-2012 with protocol no: AMRMCP/IAEC/2012/13 and experiments were carried out as per the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) (Institutional CPCSEA registration number is CPCSEA/ORG/CH/2008/Reg. no. 1219). Wistar rats were randomly distributed into three groups of six animals in each group. Before doing, all experimental animals were Methisazone fasted for 18 h and but water was given ad libitum. After collection of initial blood samples, drugs were administered in the following order. Group I – Control (0.2 mL of 0.5% carboxy methyl cellulose (CMC) sodium; p.o.) In this study, both Metoprolol tartrate and Duloxetine hydrochloride were dissolved in distilled water. Pretreatment blood sample was collected at 0 h i.e. before treatment and then remaining all blood samples were from orbital sinuses into 2 mL Eppendorf tubes containing sodium citrate as anticoagulant. Plasma was separated by centrifugation at 5000 rpm/10 min and stored at −20 °C until further analysis.

05) We therefore set a target of recruiting 2000 participants ov

05). We therefore set a target of recruiting 2000 participants over two cohorts. Female adolescents in UK school Year 11 (age 15–16 years) were recruited from 13 state-funded schools across London, England in September 2011. In 2008/9 these girls were in the first cohort to be offered the bivalent HPV vaccine at school in Year 8. A sampling

frame was used to randomly select state-funded schools that varied in terms of SES and HPV vaccine uptake. Only schools that achieved vaccine uptake levels within ±10% of the national average in 2008/9 (80%) [30] were included (n = 89), to eliminate schools where uptake might be unusually high or low for idiosyncratic reasons INCB018424 ic50 related to delivery rather than the individual characteristics that

were the focus of this study. Schools were classified as having achieved uptake rates above or below the national average. School-level SES was measured using General Certificate in Secondary Education (GCSE) attainment and Free School Meal Eligibility (children are eligible for free school meals if their parents R428 concentration are entitled to means-tested welfare benefits from the UK government [31]). Schools were classified as being above or below the national average on each of these measures [32] and [33]. Schools were randomly selected from each cell of the sampling frame and contacted via email and telephone until we reached an estimated target sample of 1000 participants, based on school roll numbers. Further details about the sampling frame have been reported elsewhere [34]. All 89 schools were sent details of the study; 13 schools agreed to participate, 19 refused due to scheduling difficulties and 57 did not respond to our initial contact and were not re-contacted because the target sample had been achieved. One year later, in September 2012, female adolescents in school Year 11 were 17-DMAG (Alvespimycin) HCl recruited from 12 of the original 13 schools; one school withdrew from the study because of scheduling difficulties. These girls were in the second cohort offered the routine HPV

vaccine at school (in 2009/10). Identical materials and methods were used during the two waves of data collection. Parents received an information sheet about the study and an opt-out form 1 week before the research took place. Parental consent was implied if the opt-out form was not returned to the school. All girls in attendance were given an information sheet and a questionnaire booklet. Consent was implied upon completion of the questionnaire and all girls were debriefed with an information sheet containing information about HPV. The study was approved by UCL research ethics committee (ref: 0630/002). Participants were asked to report their age, ethnicity, religion and, if they reported a religious affiliation, to say whether they practised their religion.

Plates were washed as described above, serum samples were seriall

Plates were washed as described above, serum samples were serially diluted 3-fold down the plate, and plates left for 2 h at room temperature. Plates were washed 3 times in wash buffer and 100 μL detection antibody Pazopanib mw was added to each well (for mouse samples HRP-conjugated rabbit anti-mouse IgG (Jackson Immuno Research,West Grove, PA), for non-human primate samples HRP-conjugated goat anti-monkey IgG (Abcam, Cambridge) and incubated for 1 h at room temperature. Plates were then washed 3 times in wash buffer and incubated for 10 min in

the dark with 100 μL per well of a TMB substrate solution (BD). The enzymatic reaction was stopped with 50 μL per well of 2 N H2SO4. Optical density was read immediately after adding stop solution on a Versamax plate reader (Molecular Devices, Sunnyvale, CA) at 450 nm with subtraction at 570 nm. Data analysis was done using SoftMax Pro v5.4 (Molecular Devices) and the half maximum values (EC50) determined to calculate antibody

titers for each sample. We screened candidate epitopes for in silico predicted broad HLA class II allele cross reactivity and high affinity binding using the immune epitope data base (IEDB) CD4 T cell prediction tool [24] and [25]. A chimeric TT/DT epitope was designed that fit these criteria. We hypothesized that inclusion of two epitopes that would induce a CD4 memory helper T cell response in vaccinated individuals may provide an either advantage over individual peptides.

A cathepsin cleavage site, either pmglp or kvsvr [26] was introduced between the epitopes with the prediction that it would ABT737 provide more efficient processing when taken up by antigen presenting cells. Pmglp was designed to be a selective cathepsin S substrate whereas kvsvr is a less selective cathepsin S, B and L substrate. Individual DT (D) and TT (T) peptides were generated (Fig. 1A) as well as a chimeric TD peptide without a cathepsin cleavage site. In addition, two chimeric peptides containing the pmglp or the kvsvr cathepsin cleavage site (TpD and TkD respectively) were also generated. The predicted reactivity of individual and chimeric peptides to 25 MHC class II alleles, as well as predicted binding affinity, and allele frequency are shown in Fig. 1B. The combined frequency of this set of alleles is predicted to have greater than 99% population coverage [25]. The predicted consensus of several algorithms is shown, where a lower score is a predictor of higher affinity binding. Scores higher than ten are not shown. Both T and D epitopes are predicted to have high affinity binding primarily across HLA-DRB1, with some binding to DP and DQ alleles. Interestingly combining the two peptides with a cathepsin linker in some cases alters the predicted binding affinity, for example HLA-DQA1*0301-DQB*0302.

In summary, the present study demonstrates ABL restriction to per

In summary, the present study demonstrates ABL restriction to permeability of the lipophilic see more compound propranolol. To avoid filter restriction, it is crucial to select a suitable filter

insert (polyester or polycarbonate) as cell growth support to assay permeability. Conducting permeability assay at multiple pH for ionizable compounds provides an alternative method to correct for the ABL effect without having to stir at a high rate during the assay; stirring will tend to compromize the cell monolayer tight junction integrity, reducing the resistance of the cell monolayer. The novel combination of a robust in vitro PBEC model and pCEL-X software provides a valuable tool to address the ABL effect as one limitation of an in vitro permeability measurement, to better reflect and predict permeation in vivo. Hence, the combination may prove a good alternative GW-572016 clinical trial to in vivo methods for BBB permeability screening. It is clear that pCEL-X is able to handle historic and literature data, but that using it in iterative mode during the design, conduct and analysis of data is even more useful, and gives additional insights into BBB permeation mechanisms. The authors confirm there are no conflicts of interest. The authors thank Dr. Adjanie Patabendige and Dr. Diana Dolman for advice and technical help on the PBEC model and permeability assays. The research was funded

by the Ministry of Education, Malaysia. “
“Visceral Leishmaniasis (VL) is a tropical disease caused by protozoan parasites of the genus Leishmania and it is transmitted by the bite of certain species of the sand fly. Also called Kala Azar, the disease is endemic in parts of north-eastern India, sub-Saharan Africa, parts of the Mediterranean, and South America.

The disease has world-wide distribution in Asia, East Africa, South America and the Mediterranean regions. It kills 200,000–300,000 people a year in the Indian subcontinent alone and is also greatly debilitating to those who survive the infection. Currently, pentavalent antimonials, amphotericin B administered through IV route, and paramomycin administered through IM route are the only first-line treatments for VL. Resistance to antimonials has reached 60% in Bihar all state in India (Sundar et al., 2000 and Sundar et al., 2012) whereas amphotericin is expensive to procure and must be given as an IV infusion in a clinical setting. Paramomycin is administered as intramuscular injection. Miltefosine is being used as an oral treatment in India, Columbia, Brazil, and Germany but major concerns exist over patient safety, compliance and suboptimal use leading to development of resistance (Olliaro et al., 2005, Romero and Boelaert, 2010 and Van Griensven et al., 2010). There is thus an urgent need for a new oral and cost-effective treatment. The Leishmania parasite resides predominantly in the liver and spleen.

While, stigmast-4-en-3-one and campesterol exhibited


While, stigmast-4-en-3-one and campesterol exhibited

peaks at 231 and 251 nm respectively. GC–MS is the most useful method for the characterization of steroids.12 and 13 Each compound was analyzed by GC–MS and identified by comparison of their mass spectra with the reference compounds in the data systems of Wiley and National Institute of Standards and Technology (NIST) spectra libraries matching. Compounds were identified with a resemblance percentage above 90%. Panobinostat in vivo Further conformation of these compounds was done by comparison of their and mass spectra with data in literature.14, 15, 16, 17, 18 and 19 Results show good agreement for the structure of campesterol (1), stigmasterol (2), (3β,5α,24S)-stigmastan-3-ol (3) and stigmast-4-en-3-one (4) as reported in the literature. On the basis of chemical and spectral evidence and upon comparison of obtained data with the literature data, the isolated compounds are identified

as campesterol (1), stigmasterol (2), (3β,5α,24S)-stigmastan-3-ol (3) and stigmast-4-en-3-one (4) ( Fig. 1) from methanol extract of the roots of C. polygonoides. All authors have none to declare. Financial support and necessary facilities offered by National Centre of Excellence in Analytical Chemistry (NCEAC), click here University of Sindh, Jamshoro, Pakistan is gratefully acknowledged. “
“Inflammation is a severe response by living tissue to any kind of injury. There can be four primary indicators of inflammation: pain, redness, heat or warmness and swelling.1 Recent studies indicate that the mediators and cellular effectors of inflammation are important constituents of the local environment of tumors.2 Medicinal plants in particular, are believed to be an important source of new chemical substances with potential therapeutic efficacy.3 Inflammation plays an important role in various diseases with high prevalence within populations such as rheumatoid arthritis, atherosclerosis and asthma. In recent years, plant materials continue to play a major

role as therapeutic remedies in many developing countries.4 Plants represent still a large source of structurally novel compounds that might serve why as lead for the development of novel drugs.5 Indigofera aspalathoides Vahl (Family: Leguminaceae) is a low under shrub commonly distributed in South India. It is commonly known as Sivanar Vembu in Southern Western Ghats of Tamil Nadu. In Indian system of herbal medicine, I. aspalathoides is specifically used for treating for Psoriasis, secondary syphilis, and viral hepatitis hepato-protective activity, kidney disorders. 6 It was reported that stem extracts of I. aspalathoides has significant anti tumor, anti inflammatory, anti viral and antimicrobial activity. 7 Global demand for herbal medicine is increasing at a rapid rate owing to their low cost and no side effects.