A descriptive study of new drug approvals during 2017-2021 and disease morbidity and mortality patterns in India.

Aim: Studies show the presence of a mismatch between drug research and disease burden. A study conducted in the European Union found that new drug development was restricted to certain diseases. A study of biosimilar approvals in India found that 87% of drugs were for treating noncommunicable diseases. This study aimed to determine the new drugs approved in India from 2017 to 2021 and the top ten causes of morbidity and mortality and detect the presence of any discordance between these. Methods: A descriptive study was conducted using data on new drug approvals accessed from the Central Drugs Standard Control Organization website. The top ten causes of mortality and morbidity in India from 2015 to 2019 were identified from the Global Burden of Diseases database. Descriptive statistics were used to compare the drug approvals and the leading diseases. Results: One hundred twenty-six drugs were approved during the study period. Antineoplastic drugs constituted 19.84% of the approvals, antimicrobials 18.25%, and cardiovascular drugs 9.52%. Ischemic heart disease and chronic obstructive pulmonary disease were the two leading causes of morbidity and mortality. Diarrheal diseases, lower respiratory tract infection, and drug-susceptible tuberculosis were among the top ten causes. Ten antibacterials, including four antitubercular drugs, were approved during this period. Two drugs were approved for rare diseases. Conclusion: Our study showed that the drugs approved were largely in line with the prevalent disease burden, and there was no significant discordance observed. Some diseases, such as ischemic stroke/intracranial hemorrhage, require further efforts in bringing forth newer pharmacotherapy options.

Dexmedetomidine attenuates lipopolysaccharide-induced renal cell fibrotic phenotypic changes by inhibiting necroinflammation via activating α2-adrenoceptor: A combined randomised animal and in vitro study.

BACKGROUND: Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models. METHODS: C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 µg/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500 µg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 µg/ml) alone, LPS and Dex (1 µM), transforming growth factor-beta 1 (TGF-ß1) (5 ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100 µM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined. RESULTS: Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-ß1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation. CONCLUSIONS: Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.

Clinical pharmacology and pharmacogenomics for implementation of personalized medicine.

With the aim of integrating clinical pharmacology with pharmacogenomics and providing a platform to gather clinicians, academicians, diagnostic laboratory personnel and scientists from related domains, the International Conference on Clinical Pharmacology and Pharmacogenomics 2023 (ICCPP 2023) was jointly organized by the Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, India and the CANSEARCH research platform in Pediatric Oncology and Hematology, University of Geneva, Geneva, Switzerland. The conference was held on 31 August and 1 September 2023, as a continued Indo-Swiss scientific exchange event series. In this report we describe the proceedings of this conference for the benefit of peers who could not attend the conference but are interested in knowing about the scientific program in detail.

Antimicrobial efficacy of Kerr pulp canal sealer (EWT) in combination with 10% amoxicillin on Enterococcus faecalis: A confocal laser scanning microscopic study.

Background: Sealers with antimicrobial properties play an important role in endodontic therapy success especially against Enterococcus faecalis infection found in failed root canal therapy. Addition of antibiotic agents to endodontic sealers may show significant increase in their antibacterial properties both against anaerobic and aerobic microbes. The purpose of the present study was to evaluate antimicrobial efficacy of Kerr pulp canal sealer (EWT) in combination with 10% amoxicillin against E. faecalis and post-root canal treatment viability of Enterococcus faecalis on the first and seventh day. Methods: A total of 60 extracted human mandibular premolar teeth were decoronated after initial decontamination with 1% NaOCl. Root length standardized to 12 mm. Canal instrumentation was done using ProTaper Universal file system till size F2 using 5.25% NaOCl. It was then infected with a pure strain of E. faecalis for a period of four days. Obturation was done using plain sealer, (n=30) and sealer-antibiotic combination, (n=30). Half of the teeth were sectioned at 24 hours (S, SA) and other half were sectioned seven days after obturation (S7, SA7). All samples were stained with SYTO9 and propidium iodide for imaging under Confocal Laser Scanning microscope. Statistical analysis was performed with the statistical software SPSS v. 17.0 (SPSS for Windows; SPSS Inc, Chicago, IL). Data was analysed using One Way ANOVA and post hoc Tukey test to determine statistical significance with p value < 0.01 considered significant. Results: Statistically significant differences were observed in green to red ratio between group S (9.561976) and S7 (0.435418) (p < 0.01). There was no difference found between SA (mean of green to red ratio, (0.70431) and SA7 (mean of green to red ratio, 0.85184). Conclusions: Antibiotics added to the sealer effectively eradicated of E. faecalis 24 hours post-obturation. However, after seven days, plain sealer was as effective as sealer-antibiotic combination.

A Review of the Safety of Interleukin-17A Inhibitor Secukinumab.

Secukinumab is an anti-interleukin (IL)-17A IgG1-κ monoclonal antibody approved for psoriasis, psoriatic arthritis, and ankylosing spondylitis. Its efficacy is well documented, but the complete safety profile of secukinumab, especially on long-term use, needs to be studied. IL-17 inhibitors increase the risk of infections, especially respiratory tract infections and candidiasis, and inflammatory bowel disease; the causal relationships are well described. However, evidence regarding the other adverse events is scarce, and causal associations between the adverse events and the biologic remain unresolved. This review aims to present a narrative perspective on the safety of secukinumab and identify some key areas where the safety of secukinumab may potentially be useful in understanding the scope of secukinumab therapy and making informed clinical decisions.

Endodontic Management of Mandibular anterior teeth and premolars with Vertucci's Type VIII canal morphology: A Rare Case.

A thorough knowledge of variable and complex tooth morphology, detailed exploration of the internal anatomy and underlying pathology, proper interpretation of radiographic images, conservative access to explore all the canals, thorough debridement and disinfection of canal system, three-dimensional seal by obturation, and good coronal seal by final restoration are essential steps in the management for a successful endodontic treatment outcome. Clinical management of rare case with extra canals in the lower anterior teeth and premolars had to undergo root canal therapy has been described. Referring to the hard-tissue repository of the human dental internal morphology, carefully interpreting multiangled radiography/cone-beam computed tomography, using tools such as magnifying loupes with illumination and ultrasonics, thermoplasticized gutta-percha system to obturate, are very helpful to the clinician can achieve this goal. This article describes and illustrates the management of a rare case with Vertucci's Type VIII canal anatomy in lower anterior teeth and premolars.

Biofilm models in endodontics-A narrative review.

The knowledge of biofilm and its eradication from the root canal system are of utmost importance in the clinical practice of an endodontist. Various treatment strategies and protocols have been demonstrated and discussed by numerous clinicians and researchers, on these models, that play an important role in the treatment outcome . Once a biofilm model is developed by considering various factors, several methods can be used to assess the biofilms formed on these models. This review discusses the importance of biofilm models in endodontics, types of biofilm models and factors associated with developing and the methods to evaluate these models.

Liver injury associated with drug intake during pregnancy.

Drug use during pregnancy is not common. Drug-induced liver injury (DILI) is a potential complication that is rare but can adversely affect both the mother and the fetus. Although many drugs can directly cause hepatotoxicity, idiosyncratic liver injury is common in pregnancy. Underreporting of adverse drug reactions, lack of adequate literature regarding drug safety in pregnancy, and the inherent difficulty in diagnosing DILI during pregnancy make the management of this condition challenging. This review attempts to describe the existing literature regarding DILI in pregnancy, which is mainly in the form of case reports; several studies have looked at the safety of antithyroid drugs, antiretroviral drugs, and paracetamol, which have an indication for use in pregnancy; the relevant data from these studies with regard to DILI has been presented. In addition, the review describes the diagnosis of DILI, grading the disease severity, assessment of causality linking the drug to the adverse event, regulatory guidelines for evaluating the potential of drugs to cause liver injury, efforts to ensure better participation of women in clinical trials and studies in pregnant women population in particular, and the challenges involved in generating adequate research evidence. The establishment of DILI registries in various countries is an encouraging development; however, there is a need for promoting active, spontaneous reporting of adverse events during pregnancy to ensure rapid generation of evidence regarding the safety of a drug in pregnant women.

The Proportion of Type 2 Diabetic Patients Achieving Treatment Goals and the Survey of Patients' Attitude Towards Insulin In tiation ini Patient s with Inadequate Glycaemic Control with Oral Anti-diabetic Drugs.

BACKGROUND: Type 2 diabetic patients often require insulin therapy for better glycaemic control. However, many of these patients do not receive insulin or do not receive it in a timely manner. OBJECTIVE: The study was planned to assess the proportion of type 2 diabetic patients attaining treatment goals as per the ADA 2018 guidelines. In addition, patient's perception of insulin therapy was assessed and compared between insulin naïve and insulin-initiated type 2 diabetic patients. METHODS: The study was conducted in type 2 diabetic patients. Data on their demographics, medical history, duration of diabetes, history of diabetes related complications, the current anti-diabetic medication received, and the most recent glycaemic parameters were all noted. Patient's perception of insulin initiation was recorded through a structured interview. RESULTS: A total of 129 patients were included in the study. Around 76.7% patients achieved HbA1c target (<7%). The duration of the disease is much higher in patients who did not meet the HBA1c target. A good number of patients felt that insulin injection would be physically painful (56.5%). The majority of the patients also felt that insulin would make their life less flexible (64.8%). Many patients have the opinion that insulin is required for life long (73.2%). More number of patients on insulin agreed with the statement 'Leads to good short-term outcomes as well as long-term benefits' compared to insulin naïve patients. CONCLUSION: The results highlight that the proportion of patients achieving the recommended glycaemic target is not satisfactory. Many patients who are inadequately controlled with oral anti-diabetic drugs were reluctant to initiate insulin.

Effects of initiating physician-performed germline testing in safety net clinic patients with epithelial overian cancer.

Germline genetic mutations occur in approximately 25% of women with epithelial ovarian cancers (EOC). We sought to determine whether newly initiated in-office oncologist-led germline testing improved time to testing and dissemination of results compared with historical controls. Patients with epithelial ovarian cancer seen between 4/1/2018 and 12/31/2019 were identified. Patients treated before genetic testing kits were made available in the gynecologic oncology clinics were compared to those treated after. Categorical variables were compared using Chi Squared and Fisher's Exact test. Cox proportional hazards model was used to compare elapsed time from testing to results. 73 patients were identified, and 502 clinic visits were analyzed. 56 (76.7%) patients were White Hispanic, 15 (20.5%) were Black, and 2 (2.7%) were White non-Hispanic. 55 (75.7%) underwent germline testing. Median time to genetic testing in the intervention group was shorter than in the control group (5, vs 24.3 weeks, 95% CI = 0-10.8 vs 14.9-33.7, p < 0.001). Among the 51 patients with genetic tests completed; results were recorded in a clinic note at 14 weeks (95% CI = 0-28.1) from first visit in the intervention group compared with 47 weeks (95% CI = 30.7-63.3) in the control group (p < 0.001). The majority of patients tested had county charity care insurance or were uninsured. Genetic testing in a safety net gynecologic oncology clinic is feasible. By initiating in-office testing, time to testing and receipt of results were meaningfully shortened. This allowed for timely identification of patients who would most benefit from PARP inhibitor maintenance therapy.

A Prospective Study of the Clinical and Demographic Profile of Type 2 Diabetes Mellitus Patients Receiving Antidiabetic Drug Combinations.

BACKGROUND: The specific treatment recommendations for type 2 diabetes mellitus (T2DM) differ based on a particular guideline. The goal of pharmacotherapy is to achieve the target HbA1c and fasting and postprandial blood glucose levels to avoid disease complications. OBJECTIVE: To evaluate the profile of T2DM patients on different antidiabetic treatment regimens and the factors leading to dose escalation in these patients. METHODS: A prospective descriptive study was conducted at Kasturba Medical College Hospital, Mangalore, a tertiary care teaching hospital, over a period of one year. The study population comprised of patients with T2DM for ≥5 years. The demographic and clinical data were collected during the baseline and follow-up visits. RESULTS: Of the 119 patients studied, 59.7% were males; 32.8% were ≥65 years of age. A significant decrease in the fasting blood glucose (FBG) on follow-up was seen (p = 0.028) in patients on sulfonylurea and metformin combination. A significant decrease in the glycated haemoglobin (HbA1c) was seen in patients on sulfonylurea with metformin and pioglitazone (p = 0.011); sulfonylurea with metformin, pioglitazone, and sitagliptin (p = 0.026); and metformin with insulin (p = 0.001). Patients who received dose escalation had a longer duration of the disease (p = 0.042), higher FBG (p = 0.039) and HbA1c (p = 0.05). CONCLUSION: A combination of metformin with sulfonylurea was the preferred first-line treatment; insulin was added when HbA1c was >9. Patients who received dose escalation had a longer duration of the disease and higher FBG and HbA1c.

Polypharmacy in Patients with Ovarian Cancer.

OBJECTIVE: Polypharmacy has been associated with morbidity and mortality in patients with cancer. Data about polypharmacy among patients with ovarian cancer are limited. The primary objective of this study was to evaluate polypharmacy in a cohort of patients with ovarian cancer and to assess the evolution of polypharmacy from initial presentation to 2 years posttreatment. A secondary objective was to evaluate differences in polypharmacy between a subset of patients primarily treated in our comprehensive cancer center (CCC) and our safety net hospital (SNH). METHODS: Women treated for ovarian cancer between January 1, 2011, and December 31, 2016, were included. Data were abstracted from the electronic medical record. Medication safety was assessed using the established Anticholinergic Burden (ACB) scale and the Beers criteria. Statistical analyses were performed using paired t tests and Cox proportional hazards models, with significance set at p < .05. RESULTS: The study included 152 patients. The majority of patients had high-grade serous carcinoma. Hypertension was the most common medical problem. The mean number of medications at the time of diagnosis was 3.72. Paired testing demonstrated significant patient-level increases in the number medications at 2 years following initial diagnosis (4.16 vs. 7.01, p < .001). At the CCC, 47.4% of patients met criteria for polypharmacy at diagnosis compared with 19.4% at the SNH (p < .001). By 2 years postdiagnosis, 77.6% of patients at the CCC met criteria for polypharmacy compared with 43.3% at the SNH (p = .001). The use of any medications on the ACB scale (p < .001) increased significantly between initial diagnosis and 2 years for the entire population. Polypharmacy was not a significant predictor of overall survival. CONCLUSION: Polypharmacy worsens as women go through ovarian cancer treatment. Both at initial presentation and at 2 years postdiagnosis, rates of polypharmacy were higher at the CCC. Polypharmacy did not have an effect on survival in this cohort. IMPLICATIONS FOR PRACTICE: Awareness of escalating numbers of medications and potentially adverse interactions is crucial among women with ovarian cancer, who are at high risk for polypharmacy.

Identifying disparities in germline and somatic testing for ovarian cancer.

OBJECTIVE: Germline mutations occur in approximately 25% of patients with epithelial ovarian cancers while somatic BRCA mutations are estimated at 5-7%. The objectives of this study were to determine the rate of germline and somatic testing in women with ovarian cancer and to identify disparities in testing at a comprehensive cancer center (CCC) and a safety net hospital (SNH). METHODS: Patients treated for ovarian cancer from 2011 to 2016 were included. Clinicopathologic data were abstracted from the electronic medical records. Logistic regression modeling were performed to calculate odds ratios (OR) and corresponding 95% confidence intervals (95%CI). RESULTS: Out of 367 women, 55.3% completed germline testing; 27.0% received somatic testing. Women at the CCC were more likely to be tested for germline (60.4% vs 38.1%, p ≤ 0.001) and somatic (34.3% vs 2.4%, p ≤ 0.001) mutations than those at the SNH. Patients with Medicare (aOR = 0.51, 95%CI 0.28-0.94, p = 0.032) or Medicaid (aOR = 0.42, 95%CI 0.18-0.99, p = 0.048) were less likely to receive germline testing than those privately insured. Patients with Medicaid were less likely to receive somatic testing (aOR = 0.15, 95%CI 0.04-0.62, p = 0.009) than those privately insured. Women with disease recurrence had a higher likelihood of being tested for germline (OR = 3.64, 95%CI 1.94-6.83, P < 0.001) and somatic (OR = 7.89, 95%CI 3.41-18.23, p < 0.001) mutations. There was no difference in germline or somatic testing by race/ethnicity. CONCLUSIONS: Disparities in both germline and somatic testing exist. Understanding and overcoming barriers to testing may improve cancer-related mortality by allowing for more tailored treatments as well as for improved cascade testing.

Evaluation of Potential Drug-Drug Interactions with Medications Prescribed to Geriatric Patients in a Tertiary Care Hospital.

BACKGROUND AND OBJECTIVES: The drugs most commonly implicated in major potential interactions are those used in the day-to-day clinical management of elderly patients with chronic diseases. This study is planned to evaluate the profile of drug-drug interactions in the medications prescribed to elderly population and also to identify the possible predictors for potential drug-drug interactions in the elderly. METHODS: This cross-sectional study included patients aged above 60 years with a minimum of two drugs in the prescriptions. Data were collected from medical prescriptions and patients' medical records. The data collected included demographic characteristics such as age, gender, height, weight, educational status, socioeconomic status, medical history, and medications prescribed. The prescriptions were analyzed for the potential drug interactions using Lexi-Interact™ Online, an online software to check drug-drug interactions. RESULTS: A total of 209 patients were included in the study, among them 104 (49.8%) were males and 105 (50.2%) were females. The mean number of medications received was 6.53 ± 2.15 per prescription. Around 138 (66%) patients received more than six medications. The mean number of potential drug interactions seen in the prescription of these patients was 3.17 ± 2.78. Around 18.2% patients had more than five drug interactions. Major drug interactions were observed in 21.42% of cases. Around 3.02% of drug interactions belonged to risk category X, i.e., to be avoided. Logistic regression analysis showed that age above 70 years was associated with the presence of drug interactions. Increased number of medication was independently associated with the occurrence of drug interactions. The presence of drug interactions was not associated with increased number of comorbidities. CONCLUSION: A significant number of potential drug-drug interactions were seen in the prescriptions of elderly patients. Increasing age and polypharmacy were identified as the predictors of potential drug interactions.

Evaluation of Adverse Drug Reaction Profile of Drugs Used as First-Line Antiretroviral Therapy.

BACKGROUND AND OBJECTIVES: The objective was to study the adverse drug reaction (ADR) profile in HIV patients receiving first-line antiretroviral therapy. METHODS: This was a prospective, observational study that included 171 HIV patients with a follow-up at six months. Demographic details, medical history, details of HIV infection including most recent CD4 count, details of antiretroviral therapy, and other concomitant medication were recorded. Adverse drug reactions were elicited by reviewing patient records and also by interviewing the patient/attendants directly. RESULTS: 171 patients completed the study out of which 88 (51.5%) were males and 83 (48.5%) were females. The study subjects included HIV-positive, treatment naïve patients who were started on treatment regimens recommended by the NACO guidelines. The ADRs observed were a fall in haemoglobin or absolute anaemia in response to zidovudine, nonspecific symptoms like headache, and a nonspecific feeling of being unwell in response to tenofovir, stavudine, and efavirenz; dyslipidaemia, pancreatitis, peripheral neuropathy, and lactic acidosis in response to stavudine; generalised rash in response to nevirapine and one case of nephrotoxicity to efavirenz. Majority of the ADRs satisfied the 'probable' category (60.1%), and the rest were "possible". ADRs to zidovudine and nevirapine superseded all others. INTERPRETATION AND CONCLUSION: Gastrointestinal effects were the most commonly observed group of ADRs, with nausea being the most common ADR, the others being gastritis and diarrhoea. The other ADRs included rash, hepatotoxicity, blood dyscrasias like anaemia, neutropenia, and thrombocytopenia, and fatigue. Few cases of lactic acidosis, peripheral neuropathy, headache, lipoatrophy, and pancreatitis were reported.

Pegaspargase hypersensitivity reactions: intravenous infusion versus intramuscular injection - a review.

Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions (HSRs) rate with IV administration. There have since been eight published reports comparing the incidence of HSRs occurring with IV versus IM pegaspargase. This review analyzes the reports and summarizes their consistent findings where feasible. For grade 3-4 HSRs, the rates are comparable with IV and IM administration. Grade 2 HSRs appear to be more likely with IV than IM administration but the validity of the difference is uncertain. Multiple factors confound the analyses, including the historically controlled nature of the comparisons and the increased likelihood of reporting adverse reactions with IV administration. In summary, the reports do not support the conclusion that pegaspargase-induced HSR rate is more frequent with IV administration.

Standardization and validation of objective structured practical examination in pharmacology: Our experience and lessons learned.

OBJECTIVES: The present study is an attempt to standardize and establish validity and reliability of objective structured practical examination (OSPE) as a tool of assessment in pharmacology. METHODS: The individual stations were standardized by establishing the blueprint of assessment, checklists for individual OSPE stations, and a review and revision of existing OSPE stations through intensive focus group discussions. Face and content validity was established by subject nonexperts and experts, respectively. Internal construct reliability was assessed using Cronbach's alpha. The scores obtained by the students during their formative sessional examinations were analyzed to calculate Cronbach's alpha, a measure of internal construct reliability and Pearson's coefficient of correlation was used to analyze test-retest reliability and interexaminer reliability. Student and faculty feedback were taken using an open-ended questionnaire. RESULTS: The Pearson's coefficient of correlation for inter-rater reliability was 0.985, P = 0.0001. The Pearson's coefficient of correlation for test-retest reliability was 0.967, P = 0.0001. Cronbach's alpha values for first, second, and third sessional examinations were 0.825, 0.724, and 0.798, respectively. CONCLUSION: The faculty and student feedback received was constructive and enabled a systematic review of the existing method and also served as a means to revise the existing curricula.

Can Metabotropic Glutamate Receptor 7 (mGluR 7) be a Novel Target for Analgesia?

INTRODUCTION: The present study was carried out to study the role of metabotropic glutamate receptor 7 (mGluR7) using its agonist, N,N'-bis(diphenylmethyl)-1,-ethanediamine (AMN082) for nociceptive stimuli, in animal models. By conducting this research, we aim to introduce a novel target for acute pain management. OBJECTIVE: To study the role of metabotropic glutamate receptor 7 (mGluR7), in analgesia, using mGluR7 agonist AMN082 in animal models. MATERIALS AND METHODS: Swiss albino mice of either sex, weighing 20-30gm were used for the study. The animals were divided into 3 groups with 6 mice in each group: Control or Normal group received 0.5% methylcellulose in normal saline; Standard group received the drug tramadol HCl at 40mg/kg; and test group received drug AMN 082 at 5mg/kg. All the drugs were administered by intraperitoneal route. Hot plate test and Tail flick test were done to evaluate the analgesic effect of the drug. Reaction time for the end points in both the models were noted before drug administration at 0 min and after drug administration at 15, 30,60,90 and 120 min. Statistical analysis was done using One-Way-ANOVA followed by Tukeys post hoc test. p-value was considered significant at ≤ 0.05. RESULTS: The group that received AMN082 showed significantly lesser reaction time compared to normal and standard groups in both the analgesia models. CONCLUSION: The mGluR 7 stimulation by an agonist AMN082, did not show analgesic effect but induced hyperalgesia in response to thermal nociceptive stimuli.