The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists

CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors. Both compounds inhibit CRF-stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic-like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic-like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress-induced increases in plasma CORT secretion but at doses 3-4-fold greater than those required for anxiolyticlike efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic-like doses, DMP696 and DMP904 occupy >50% CRF(1) receptors in the brain. The in vivo IC(50) values (plasma concentrations required for occupying 50% CRF(1) receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC(50) values. Neither compound produces sedation, ataxia, chlordiazepoxide-like subjective effects or adverse effects on cognition at doses 10-fold higher than anxiolytic-like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic-like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.     

Effects of BCG Vaccination on Evolution of Leprosy

Background

BCG vaccine is considered to have immunoprophylactic potential in leprosy. However controversy exists about the extent of prophylaxis it provides. In view of this, a study was undertaken to see the evolution of disease in established cases of leprosy who were already vaccinated with BCG and to compare it with the cases of leprosy who were not vaccinated with BCG.

Methods

114 newly diagnosed cases of leprosy were studied. Patients were divided into two groups-BCG vaccinated and non-vaccinated. Clinical diagnosis of leprosy was confirmed by bacteriological and histopathological studies in each case. All patients were given standard anti leprosy treatment and were evaluated monthly for a minimum period of one year.

Results

All the cases were males in the age group of 20 to 50 years. 25.4% of cases had received BCG vaccine and 74.6% were not vaccinated for the same. No significant difference was observed in the incidence of different types of leprosy in vaccinated and non-vaccinated groups. 25.9% cases in non-vaccinated group developed lepra reaction as compared to 13.8% in vaccinated group. The incidence of deformities and disabilities in vaccinated group was only 10.3% as against 18.8% in non-vaccinated group. The rate of bacillary clearance appeared faster in vaccinated group.

Conclusions

Although there is no significant difference in the pattern of different types of leprosy in BCG vaccinated and non-vaccinated cases, there is reduction in the incidence of reactions as well as deformities and disabilities in BCG vaccinated cases as compared to non-vaccinated cases.Key Words: BCG Vaccine, Leprosy     

Correction of Lower Limb Deformities Using Ilizarov's Technique

Background

India accounts for approximately 10 million orthopaedically handicapped children and adults with limb deformity. Ilizarov ring fixator could treat most of these deformities.

Methods

Twenty cases of deformities of lower limb managed with Ilizarov technique during period between March 2001 and February 2003 were studied.

Results

55% were in the age group of 11-30 years. Out of the 20 cases studied, 6 were congenital talipes equino varus, 8 were fixed flexion deformity of knee, 4 were equines deformity of the ankle and 2 were malunited fracture shaft of tibia.4 patients who had recurrence were operated for fixed flexion deformity of the knee. The main complication encountered was pin tract infection, which was seen in 15(75%) cases. In 16(80%) cases, the results were excellent with no recurrence of deformity and patients were able to walk independently. In 4 (20%) cases, recurrence was mild to moderate (10 to 20) but all of them were able to ambulate idependently and carry out their routine activities.

Conclusion

Ilizarov ring fixator is a superior compared to conventional methods for correction of deformities of lower limb.Key Words: Ilizarov method, Ligamentotaxis, Distraction     

Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation

In 1999, ISPOR formed the Quality of Life Special Interest group (QoL-SIG)--Translation and Cultural Adaptation group (TCA group) to stimulate discussion on and create guidelines and standards for the translation and cultural adaptation of patient-reported outcome (PRO) measures. After identifying a general lack of consistency in current methods and published guidelines, the TCA group saw a need to develop a holistic perspective that synthesized the full spectrum of published methods. This process resulted in the development of Translation and Cultural Adaptation of Patient Reported Outcomes Measures--Principles of Good Practice (PGP), a report on current methods, and an appraisal of their strengths and weaknesses. The TCA Group undertook a review of evidence from current practice, a review of the literature and existing guidelines, and consideration of the issues facing the pharmaceutical industry, regulators, and the broader outcomes research community. Each approach to translation and cultural adaptation was considered systematically in terms of rationale, components, key actors, and the potential benefits and risks associated with each approach and step. The results of this review were subjected to discussion and challenge within the TCA group, as well as consultation with the outcomes research community at large. Through this review, a consensus emerged on a broad approach, along with a detailed critique of the strengths and weaknesses of the differing methodologies. The results of this review are set out as "Translation and Cultural Adaptation of Patient Reported Outcomes Measures--Principles of Good Practice" and are reported in this document.     

Response of Recurrent Binge Eating and Weight Gain to Topiramate in Patients with Binge Eating Disorder after Bariatric Surgery

Background: The effectiveness of topiramate was evaluated in the treatment of recurrent binge eating and weight gain in patients with binge eating disorder (BED) and obesity who had undergone initially successful bariatric surgery. Methods: The records of 3 consecutive patients with BED and obesity who presented to our clinic with recurrent binge eating and weight gain after undergoing initially successful bariatric surgery were reviewed. They were treated with topiramate for an average of 10 months. Results: All three patients reported complete amelioration of their binge eating symptoms and displayed weight loss (31.7 kg in 17 months, 14.5 kg in 9 months, 2 kg in 4 months, respectively) in response to topiramate (mean dose 541 mg). Conclusion: Although anecdotal, these observations suggest that topiramate may be an effective treatment for patients with BED and obesity who experience recurrent binge eating and weight gain after initially successful bariatric surgery.     

Examination of the clock gene Cryptochrome 1 in bipolar disorder: mutational analysis and absence of evidence for linkage or association

Bipolar disorder is associated with malfunctions of the circadian system, which regulates individual circadian rhythms and which enables the adaptation to a daily 24-h cycle and seasonal change. One of the human circadian clock genes, cryptochrome 1 (Cry1) (located on 12q23-q24.1) was analyzed because of its close correspondence to a linkage hotspot for bipolar disorder.We found no evidence for linkage of 52 bipolar families to two Cry1 flanking microsatellites under several parametric and non-parametric models. In order to employ association for a more sensitive test, 25 affected subjects selected from families with positive LOD scores were screened for mutations by sequencing 9.5% of the Cry1 gene. A total of 16 single nucleotide polymorphisms (SNPs) and a 3 base pair insertion were identified. However, no mutations with probable functional impact were found. These novel SNPs and data on allele frequency and linkage disequilibrium structure will be useful for future association analyses. Nine SNPs have been analyzed in a set of 159 parent proband triads. Linkage disequilibrium analyses using single SNPs and haplotypes showed no association to bipolar disease.Additional, more powerful, studies involving Cry1 and other circadian clock genes need to be tested before an association of circadian abnormalities with bipolar disorder can be excluded.     

Reproductive function and risk for PCOS in women treated for bipolar disorder

INTRODUCTION: This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications. METHOD: Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples. RESULTS: Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used. CONCLUSIONS: Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.     

Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats

Corticotropin-releasing factor(1) (CRF(1)) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF(1) receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.     

Effect of short-term Psychiatric Intervention in Cancer Patients

A total of 50 patients undergoing cancer treatment at Malignant Disease Treatment Centre were included in the present study aimed at evaluating the psychological status of cancer patients. All patients filled a specially designed proforma and the following psychological questionnaires : General Health Questionnaire, Carroll Rating Scale for Depression, State-Trait Anxiety Inventory, PGI General Well-being Scale and Quality of Life Scale. Analysis of the results showed that 22 (44%) of the cancer patients had psychiatric disorders and this number had reduced to 12 (24%) after therapy. The difference was statistically significant. Psychiatric treatment also resulted in a statistically significant reduction in level of depression as measured by Carroll Rating Scale for depression. Short term psychiatric treatment was found to be very useful in treating psychiatric morbidity and depression in cancer patients.Key Words: Cancer, Depression, Psychiatric morbidity