Figure 3. Phase I metabolism of haloperidol. CPHP, chlorophenyhydroxypiperidine; CR, carbonylreductase; FBPS, fluorobutyrophenon acid; HPP+, haloperidol pyridinium; RHPP+ reduced HPP+. The new atypical antipsychotic risperidone is also metabolized by cytochrome CYP2D6. Patients who are homozygous

to the CYP2D6*4 allele, ie, slow metabolizers, also show higher plasma levels. Furthermore, schizophrenic Inhibitors,research,lifescience,medical patients who were heterozygous for cytochrome CYP2C19 and CYP1A2 had fewer side effects. Cytochrome CYP1A2*1F seems to be important too. Using the PANSS (Positive and Negative Symptom Scale), a poorer therapy response regarding the negative symptoms could be seen in homozygous CYP1A2*1F Alectinib cost allele patients. Pharmacokinetic aspects are also responsible for the plasma levels of other drugs, eg, amisulpride. Tenfold differences in the amisulpride plasma level can be measured at the same dosage. We found the same results for the atypical antipsychotic clozapine and also for other antipsychotics, Inhibitors,research,lifescience,medical such as risperidone. Too low and too high plasma levels reduce the therapy response and arc the reason for many side effects at high plasma levels. Multidrug resistance protein On Inhibitors,research,lifescience,medical the pharmacokinetic

level, drug nonresponse can also occur via mechanisms affecting the efflux of a diverse range of drugs out of the cells or the permeability of the blood–brain barrier. These mechanisms have evolved during cell evolution in order to protect, against toxic environmental substances or metabolites. The extensively described efflux mechanism is mediated via P-glycoprotein(P-gp)or MDRl. Multidrug resistance in humans is caused by the overexpression of the multidrug transporter: P-gp/MDR1.This overexpression can be induced by drugs affecting the MDR1 gene transcription or via functional Inhibitors,research,lifescience,medical genetic polymorphisms. P-gp is an adenosine triphosphate (ATP)–dependent transmembrane efflux pump present in the hepatic, renal, and endothelial

cells forming the blood-brain barrier. The only common structural feature of MDR1 substrate compounds identified so far is their relatively hydrophobic and amphipathic Inhibitors,research,lifescience,medical nature. Risperidone and quetiapine are relatively good substrates to the P-gp, whereas haloperidol, clozapine, and flunitrazepam are hardlytransported or not at all.10 So far, a total of 28 SNPs has been found on the MDR1 gene. Interestingly, the C2435T polymorphism, which causes no amino acid change, Tryptophan synthase has been found to be associated with duodenal expression of MDRl.11,12 The C2435T mutation is located in an noncoding promoter position (exon 26) of the MDR1 gene13 and is therefore unlikely to be the only cause of this effect. Up to now, the results of worldwide clinical studies are still inconsistent regarding the association of the C2535T polymorphism with MDR1 expression, making further investigations necessary. N-Acetyltransferase Acetylation by NAT is a phase II conjugation reaction. It is controlled by two autosomal alleles at a single gene locus.

2000). In contrast to most other main nerve trunks, the first and second trigeminal branches are purely sensory, and the motor (masticatory) component of the third branch is distinctly separated from the sensory component by a thick perineurial sheath, from the trigeminal root to the proximal part of the branch. Moreover, there are several human pain conditions that affect specifically the trigeminal nerves and a differential

Inhibitors,research,lifescience,medical sensitivity to certain drugs in neuropathic pain in the trigeminal versus other territories has been observed (Idanpaan-Heikkila and Guilbaud 1999; Watson 2004). It is therefore valuable to develop specific animal models for the Protein Tyrosine Kinase inhibitor orofacial area. This review presents an overview of the rodent models developed for the trigeminal area over the last 20 years, with the emphasis on behavioral tests. To date, most reviews have overviewed the mechanistic

components of trigeminal Inhibitors,research,lifescience,medical pain but none have focused specifically on the various behavioral testing methods available in rodents. For reviews which specifically elucidate the mechanisms of orofacial pain, see for example Sessle (2005), Inhibitors,research,lifescience,medical Hargreaves (2011), Takeda et al. (2011), Iwata et al. (2011). The scope of this review will span basic research on the rodent skin and mucosa, and muscular and articular sensory territories of the trigeminal Inhibitors,research,lifescience,medical nerve that has been published in the last few decades. For reasons of simplicity, and because these topics have already been broadly discussed in the literature, models that involve specific target organs such as teeth, the eye, and salivary glands will be omitted. Useful reviews and reports are available on dental pain (Cooper

and Desjardins 2010; Tarsa et al. 2010; Hargreaves 2011), eye pain (Tashiro et al. 2010; Marquart 2011), and salivary gland pain (Ogawa et al. 2003). Cancer pain has certain inflammatory components and sometimes some neuropathic pain aspects (Mantyh et al. 2002; Benoliel et al. Inhibitors,research,lifescience,medical 2007). The behavioral evaluation methods used in animal models of orofacial cancer pain are similar to those used in other orofacial pain models (Nagamine et al. 2006; Ono et al. 2009; Harano check et al. 2010) and this topic will also not be explored in this review. Finally, chronic primary headaches, including migraines, fall into craniofacial disorders but are not usually considered “orofacial” conditions1 (Zakrzewska 2009) and thus will not be discussed. Of particular interest will be models of TN, TMD, and facial muscle pain and other models of cutaneous nociception in rodent orofacial pain. While several recent reviews have summarized some of the techniques used to induce neuropathic or inflammatory pain in the facial region (Khan and Hargreaves 2010; Iwata et al.

This is a cost-effective method of performing GWASs and has proved to be effective in identifying disease genes (eg, refs 31,32). However, due to errors in DNA quantification, this method is less sensitive than individual genotyping and has less power. Furthermore, the evaluation of data is limited to the study of (estimated) allele frequencies at the level of individual SNPs. This method does Inhibitors,research,lifescience,medical not detect the effect of haplotypes, interactions between SNPs, or the effects of genotypes that do not show differences in allele frequencies. The first individual-genotyping-based GWAS of schizophrenia involved a very small sample of 178 cases and 144 controls.29 The best hit was for a variant

near the colony-stimulating factor-2 Inhibitors,research,lifescience,medical receptor alpha (CSF2RA) gene, but this did not achieve genome-wide significance.29 The second GWAS of this type included 738 patients and 733 controls. Although a few signals coincided with genomic regions that had been implicated in previous linkage studies of schizophrenia, this study found no genome-wide Inhibitors,research,lifescience,medical significant association.30 O’Donovan et al initially performed a GWAS using a moderately sized patient sample (n=479). They then performed

a follow-up study of 12 markers with a P value ≤ 10-5 in a much larger sample to enhance the statistical power.25 Strong evidence for replication was obtained for 3 of these 12 markers (P ≤ 5 x 10-4), although the best supported variant Inhibitors,research,lifescience,medical still failed to achieve genome-wide significance (Table I) . The highest-ranking SNP identified in this study is located in an intron of the zinc finger protein 804A gene (ZNF804A), a putative transcription factor which had never been implicated previously in the risk for schizophrenia. The case sample was Inhibitors,research,lifescience,medical then extended to include bipolar patients. The P value for the total sample surpassed the level of genome-wide significance (P=9 x 10-9). The association between ZNF804A and schizophrenia has recently been VX-809 manufacturer replicated by the International Schizophrenia Consortium,24

and ZNF804A is therefore a promising susceptibility gene for schizophrenia. A recent imaging genetics study of ZNF804A risk genotypes has provided evidence in support of these genetic findings. This study demonstrated that healthy carriers of ZNF804A risk genotypes display pronounced genedosage-dependent alterations in functional coupling between the hippocampus and the dorsolateral prefrontal cortex (DLPFC) across the those two hemispheres, which mirrors findings in patients.33 Table I Published genome-wide association studies (GWASs) for schizophrenia.21-30,32 The number of variants investigated, the best associated single-nucleotide polymorphism(s)-SNP(s) – found and the gene(s) containing the SNP(s), the corresponding Pvalue(s), … Three recent multicenter studies have provided important insights. The initial findings of these three studies failed to surpass the level of genome-wide significance.

35 The µ-pioid receptor gene OPRM1 is the most extensively studied of the opioid receptor genes because of its important role in reward mediated by endogenous opioids. The functional

OPRM1 Asn40Asp variant of the µ-opioid receptor gene has been shown in some studies to be associated with opioid addiction.36-37-38 For example, association of this OPRM1 variant to polysubstance abuse including opioids, cocaine, and alcohol was reported by Kranzler et al.36 Berrettini and colleagues Inhibitors,research,lifescience,medical reported that the major opioid preference quantitative trait loci in mice mapped to the location of the murine µopioid receptor gene.39 OPRM1 Asn40Asp has also been variably linked to alcoholism,29,30 and perhaps most intriguingly, appears to alter opioid-mediated release of Cortisol, this effect on the hypothalamicpituitary-adrenal axis potentially revealing its action on stress activations important in addiction.40 A delta opioid receptor, OPRD1, variant has also been reported to be associated with substance dependence.41 The endogenous Inhibitors,research,lifescience,medical opioid systern is also critical to the reinforcing effects of nonopioid drugs including nicotine, alcohol, cocaine, and cannabinoids.37,42 Inhibitors,research,lifescience,medical Gene-environment interactions in addiction Addiction is a complex disease involving the interaction of genes and environment. The vulnerability to abuse of addictive

agents is in part determined by genetic variation and in part by environmental factors including exposure to EGFR activation addictive agents, but also such nonspecific factors as stress exposure early in life. Several of the interacting genes found so far are stressrelated, Inhibitors,research,lifescience,medical modulating resiliency and vulnerability. Early life stress exposures such as childhood sexual abuse play a powerful but apparently Inhibitors,research,lifescience,medical nonspecific role, because such stress also increases vulnerability to other psychiatric diseases. In the rat preferring/nonpreferring (P/NP) model of alcohol consumption, a major quantitative locus for ethanol preference is at the site of the gene for neuropeptide Y, an anxiolytic neuropeptide. In the human,

genetic variants of neuropeptide Y have sometimes, first but not always, been linked to alcoholism as well as other behaviors, including obesity.43-44 A catechol-O-methyltransf erase polymorphism that predicts anxiety and cognitive function has been associated with alcoholism and polysubstance abuse.45 Another stress-related gene is the serotonin transporter, which contains the functional HTTLPR locus. In the rhesus macaque monkey, the reduction of function allele of the orthologous rh-HTTLPR locus predicts enhanced alcohol consumption, but only in the context of early life stress exposure.46 In humans with cocaine addiction, the already high rate of suicide attempts is greatly increased in carriers of the reduction of function HTTLPR allele who had a history of childhood abuse or neglect.

The established role of GABA-ergic signaling as a major tonic

inhibitor of stress responses provides plausible explanation for the capacity of GABA/benzodiazepine antagonists to induce several behavioral and endocrine correlates of stress or augment the responsiveness to systemic and emotional challenges.67 Although endogenous opioids definitely contribute to several aspects of the Inhibitors,research,lifescience,medical response to stress, divergent effects of opioid administration on neuroendocrine parameters, also due to intricate interactions with other neurotransmitter systems, appear to be somewhat at odds with the reigning opinion that opioids tonically suppress the LHPA axis.68 It is thus helpful to consider that the issue discussed herein concerns pharmacological effects with abrupt onset, which are not Inhibitors,research,lifescience,medical expected to produce immediately dramatic shifts in what is called “opioidergic tone.” An abridged statement in the context of this paper summarizes that (i) acute administration of morphine or receptor-selective

Inhibitors,research,lifescience,medical opioid agonists results in distinct stresslike changes of neuroendocrine end points and (ii) similar phenomena occur after spontaneous or antagonistprecipitated withdrawal from chronic opioid treatment. As with several other opioid-sensitive systems, development of tolerance is accompanied by attenuated responsiveness of the LHPA axis to subsequent opioid administration. The effects of psychomotor stimulants, as exemplified by cocaine69 and amphetamine,70 include stress-like symptoms of behavioral disruption and defensive withdrawal and stimulation of hypothalamo-pituitary-adrenal Inhibitors,research,lifescience,medical secretions. Most of these effects and the stress-contrasting suppression of prolactin

release are ascribed to their agonistic influence on central monoaminergic transmission. Elevation of circulating ACTH Inhibitors,research,lifescience,medical and selleck compound glucocorticoid concentrations has been demonstrated following intracerebral cannabinoid treatment; however, the involvement of drug-specific signaling mechanisms remains unclear, as specific cannabinoid receptor antagonists have produced biphasic effects. Alcohol administration powerfully stimulates the LHPA axis71 and potentiates defensive responses. As with opioids, endocrine changes in the course of chronic treatment either are suggestive of the development of selective tolerance. In view of its essential role in the initiation and integration of behavioral, autonomic, and endocrine responses to stress, exogenous CRH dependably mimics several consequences of stressful stimuli. It should be added, however, that the stressogenic action of CRH is warranted following intracerebral administration, while some divergence (eg, in cardiovascular effects) may occur following systemic application.

Performance status was recorded using the Palliative Performance Scale (PPS) [19]. All assessments were conducted between 0900 h and 1300 h. All participants were asked to refrain from smoking and caffeine ingestion on the morning of assessment, but were not asked to stop any of their usual medications or fast. A physician and research nurse performed the tests of autonomic function in a quiet room at ambient

temperature (21-23 C). Autonomic function tests were carried out using a modified Ewing’s battery [17]. Heart rate was measured by ECG Inhibitors,research,lifescience,medical using standard limb leads; heart rate (HR) tests were excluded if invalidated by arrhythmia, excessive ectopic activity or movement artefact. Blood pressure (BP) was monitored using the

Finometer Pro device (Finapres Medical Systems BV, Amsterdam, the Netherlands) which enables noninvasive Inhibitors,research,lifescience,medical beat-to-beat BP measurement from finger arterial BP. The BP recordings are derived from the circumferential pressure generated by a finger cuff, which is varied to maintain a constant digital arterial size, as measured Inhibitors,research,lifescience,medical by a photoplethysmograph. Under such conditions the external cuff pressure equals the internal digital arterial pressure [20]. Participants rested in the supine position for at least ten minutes before testing. During this time they were covered with a blanket and wore a thermal mitten with glove liner in order to improve BP signal pick-up. Blood pressure tests were excluded if the trace was obscured by movement artefact or artefact due to external pressure on the finger-cuff. Parasympathetic tests 1. Deep breathing Whilst supine, participants were requested to ‘take slow Inhibitors,research,lifescience,medical deep breaths, so that each breath in lasts five seconds and each breath out lasts 5 s, for a total of six consecutive breaths’. This was rehearsed prior to testing and the Onalespib in vitro tester guided the timing of the breaths for the participant Inhibitors,research,lifescience,medical by verbally counting through each of the six breaths/cycles. The maximum and minimum HR during each breathing cycle was calculated from the corresponding shortest and longest R-R interval, and the response recorded as the mean of the differences during

three successive breathing cycles. 2. Active stand Participants were requested to stand up from the supine position as quickly as possible ADAMTS5 and to remain standing, in silence, for three minutes, with the monitored arm resting by their side. Assistance with rising was provided when this could not be achieved independently. Heart rate response was measured as the ratio of the maximum R-R interval at or around the 30th beat after starting to stand, to the minimum R-R interval at or around the 15th beat. 3. Valsalva manoeuvre The valsalva manoeuvre was achieved by forced expiration, against an open glottis. Participants were requested to achieve a constant pressure of 40 mmHg for 15 s. The procedure was rehearsed prior to testing and the tester guided the participant by counting aloud through the fifteen seconds.

2 mm thickness, matrix: 128 × 128; FOV: 256 × 256 mm2. Diffusion gradients were encoded in 12 directions with a b values of 1000 s/mm2 and an additional image with no diffusion gradient (b = 0 s/mm2). Three sets of DTI data were acquired for average and the total DTI acquisition time was 5 min 47 sec. To improve the signal-to-noise ratio (SNR) for the Inhibitors,research,lifescience,medical DTI images, the three separate sets of images were averaged automatically by the “Neuro3D task card” (Siemens Syngo). We determined the SNR according to Kasprian et al. (2008). The SNR is defined as the mean

value of the signal of a circumscribed WM region of the fetal brain on diffusion unweighted (b = 0 s/mm2) images divided by the standard deviation determined Inhibitors,research,lifescience,medical in the same region. A b value of 1000 s/mm2 was used in fetal DTI as Huang et al. (2009). This value was adapted to high ADC values expected at the fetal WM in order to the formula 1.1 per ADC that have been thought to provide the best contrast-to-noise ratio (Dudink et al. 2008). Data postprocessing Diffusion tensor parameters DTI calculation and postprocessing were performed after transferring diffusion-weighted images to a Siemens off-line workstation, using the “DTI task

Card” Inhibitors,research,lifescience,medical software, and the four classical parameters were computed: the longitudinal diffusivity (λ// or λ1), the radial diffusivity λ = (λ2+λ3)/2, the ADC, and the FA. Definition of seed Inhibitors,research,lifescience,medical regions and tractography Seed regions for DTI tractography were determined based on anatomical landmarks observed on the ADC and FA color-coded directionality maps (Figs. 2 and ​and3).3). Using the “Neuro3D task card” (Siemens Syngo), each axes of the MPR (multi-planar reconstruction) was rotated (double oblique) to get axial, coronal, and sagittal planes in the anatomical referential for each fetus. ADC maps provided a good contrast, and the overlay of color-coded FA helped to depict coherent Inhibitors,research,lifescience,medical fiber

pathways nearby the ROIs by indicating fiber direction and degree of anisotropy. However, because the fetus head in utero is randomly positioned relative to the scanner referential, the color code used in this study did not correspond to the regular color code obtained in see more adults with standard positioning (red: right–left, green: antero–posterior, blue: supero–inferior) (Pajevic and Pierpaoli 1999). The “Neuro3D DTI task card” did not allow to apply tensor however rotation to keep this conventional color code. Figure 2 Diffusion tensor tractography method used to depict cortico-spinal tract (CST), optic radiations (OR), and CC bundles. Regions-of-interest (ROIs) were delineated based on anatomical landmarks observed on ADC and FA color-coded directionality maps. (A) … Figure 3 Example of DTI tractography of CST and OR obtained in utero and in vivo for fetal brain.

There are other essential goals in clinical trial design as well. For instance, a well-designed trial will have a sample size that provides adequate statistical power to ABT 737 detect a clinically meaningful effect. An antidepressant trial, for example, must be designed to detect an effect of about .40 standard deviation units (ie, Cohen’s d=.40) and that requires about 100 participants per

treatment group for 80% statistical power for a t-est with a two-tailed alpha-level of .05. However, there is a tradeoff between power and feasibility. Recruitment of 100 per group is only feasible if compatible with both the budget and Inhibitors,research,lifescience,medical the study site patient flow. Furthermore, a trial must be designed such that the false-positive rate (ie, Type I error) is acceptable; the convention is 0.05. This is because false-positive treatments, of course, do not reduce suffering in patients. Finally, the design must be applicable. That is, Inhibitors,research,lifescience,medical the recruited sample should yield results Inhibitors,research,lifescience,medical that generalize to the target patient population; ie, that for which the indication is sought. A well-designed and well-implemented RCT is the gold standard for treatment evaluation. This is because the groups tend to be well-balanced at baseline,

and therefore subsequent group différences can be attributed to treatment effects, providing strong internal validity. However, there are limitations of results from RCTs for psychiatric Inhibitors,research,lifescience,medical disorders. For example, trials for mood disorder interventions typically involve short-term treatment (4 to 12 weeks) despite the chronic nature of the disorders. Furthermore,

Inhibitors,research,lifescience,medical the samples tend to be highly- selected and that restricts the generalizability (ie, external validity) of the results. For instance, it has been shown that RCTs for major depression evaluate treatment in rarefied samples, excluding as many as 85% of those who are until screened.3 The exclusions are, for example, based on illness severity (too severe or not severe enough) and safety risk (eg, suicidality, concomitant medication, or psychosis). Therefore the results do not inform the treatment of patients who have such features. Finally, the attrition poses a serious threat to the internal validity of a clinical trial. The attrition rates in antidepressant trials range from 30% to 40% and they are higher for antipsychotics, ranging from 50% to 60%:’ Self-selection of this type (ie, attrition) and of this magnitude severely compromises randomization. Features of design and analysis that reduce the impact of attrition on RCTs of psychotropics have been discussed in detail elsewhere.

Invasive Selleck BYL719 colorectal carcinoma also frequently shows characteristic necrotic debris in glandular lumina, so-called “dirty necrosis” (Figure 3). This unique feature can be quite useful to suggest a colorectal primary when a metastasis of unknown origin is encountered. Figure 2 Desmoplastic reaction characterized by proliferation of spindle cells surrounding an adenocarcinomatous gland (original magnification ×400)

Figure 3 Necrotic debris (“dirty necrosis”) within the lumina of adenocarcinomatous glands (original magnification ×400) It should be noted that when a diagnosis of invasive carcinoma is rendered, it means that carcinoma has at least invaded into the Inhibitors,research,lifescience,medical submucosa of the colorectum. This differs from the concept of invasion in other parts of the gastrointestinal tract (esophagus, stomach and small intestine), where the presence Inhibitors,research,lifescience,medical of mucosal invasion is sufficient for the diagnosis of invasive carcinoma (pT1). In the colorectum, submucosal invasion is required for the diagnosis of a pT1 tumor. For reasons Inhibitors,research,lifescience,medical that are not entirely clear but generally thought to be due to the relative paucity of lymphatics, invasion confined to the lamina propria and muscularis

mucosae has no risk of nodal or distant metastasis. Thus, intramucosal carcinoma is preferably called high grade dysplasia (discussed later) by pathologists in order to avoid unnecessary surgical intervention. In the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (9), mucosal Inhibitors,research,lifescience,medical invasion is classified as carcinoma in situ (Tis). Nevertheless, the term of intramucosal carcinoma may still be used by some pathologists. No matter what term is used by pathologists, the identification of high grade dysplasia or intramucosal Inhibitors,research,lifescience,medical carcinoma in a biopsy or polypectomy specimen should not affect the decision-making for patient management. The decision to perform surgical resection should be ultimately determined by the gross appearance of the lesion, endoscopic ultrasound

findings, and endoscopic resectability. Histologic variants In World Health Organization (WHO) classification, a number of histologic variants of colorectal carcinomas are listed, such as mucinous, signet ring cell, medullary, micropapillary, serrated, cribriform comedo-type, adenosquamous, spindle cell, and second undifferentiated. Only the first 3 variants are discussed here. Mucinous adenocarcinoma This special type of colorectal carcinoma is defined by >50% of the tumor volume composed of extracellular mucin (3). Tumors with a significant mucinous component (>10%) but <50% are usually termed adenocarcinoma with mucinous features or mucinous differentiation. Mucinous adenocarcinoma typically shows large glandular structures with pools of extracellular mucin (Figure 4). A variable number of individual tumor cells, including signet ring cells, may be seen.

In groups 2, the right eyes received two drops of 3% acetylcysteine from day 1 (for one week), and one drop of 3% acetylcysteine and one drop of 0.1% dexamethasone from day 8 (beginning

of week 2). In group 3, the right eyes were treated with two drops of 3% acetylcysteine from day 1 (for two weeks), and with one drop of 3% acetylcysteine and one drop of 0.1% dexamethasone from day 15 (beginning of week 3). Control eyes in all groups received two drops of isotonic saline (NaCl 0.9%). All eyes were treated six times per day (once every two hours from 8 am to 6 pm) for 28 days. The wounds were stained by fluorescein at 4 pm every day in order to record by photography, then the defect Inhibitors,research,lifescience,medical area (in mm2) was Inhibitors,research,lifescience,medical calculated using the AutoCAD 2005 program. Healing was considered to be complete when no fluorescein stain uptake was visible with a cobalt light source. All eyes were thoroughly examined to assess the corneal haze at two and three months after the beginning of surgery. The daily healing was calculated for each eye using the following formula: [(Wound area on each day – wound area on the next day)/ wound area on that day]×100

Corneal haze was categorized as cornea without opacity, mild opacity, moderate opacity, or severe opacity based on light transmission Inhibitors,research,lifescience,medical and visibility of the fundus by the same examiner throughout the study. Every month for three months Inhibitors,research,lifescience,medical from the beginning of the study two rabbits in each group were deeply anesthetized and both of their eyes were enucleated. The eyes were then immersed immediately in 10% buffered formalin, processed, and sectioned with a microtome at five µm thickness. The sections were stained with hematoxylin and eosin, and examined by light microscopy. They were examined for the epithelial changes (MAPK Inhibitor Library molecular weight hypertrophy and hyperplasia), noevascularizations, stromal irregularity and edema, scarring of

stroma and cellular changes. Statistical Analysis The mean daily healing against time (days) were fitted Inhibitors,research,lifescience,medical to a linear regression equation and slope of healing curves were calculated for each group. The slopes of healing Phosphoprotein phosphatase for the control (those receiving saline) and treated (those receiving drugs) eyes of each group was compared using Wilcoxon signed ranks test. Similar test was also used to compare total healing time or corneal haze in the control and treated eyes of each of the three groups.18 Results Macroscopic Evaluation Analysis of 36 healing curves and their slopes revealed that the mean healing time or mean daily healing between of control and treatment eyes in group 1 (NAC+Dexa1) was significant (table 1 and figures 1​1–​-3).3). These findings show that drug combinations increased the mean healing time and decreased mean daily healing compared with the control eyes (P<0.05). However, mean healing time or mean daily healing of the control and treatment eyes in group 2 (NAC+Dexa8) or group 3 (NAC+Dexa15) was not significant.