Changes In Clinical Signs Research Articles

Predictors of treatment failure and clinical stability in patients with community acquired pneumonia.

Community acquired pneumonia (CAP) is the leading infectious cause of mortality worldwide with approximately 10% of patients hospitalized requiring intensive care unit (ICU) admission. The ability to predict clinical stability (CS) and treatment failure (TF) enables the clinician to alter antibiotics appropriately, facilitate a timely ICU admission, or arrange a suitable discharge. The detection of CS and TF can be difficult and changes in clinical signs may be subtle or delayed. Thus clinical scores and biomarkers are routinely used to identify severity and monitor clinical progression. The evidence, however, is vast and the definitive role of these systems is at times difficult to elucidate. The aim of this review is to analyse the current literature and to provide a rational and clinically focused view of the predictive utility of various systems used to identify CS and TF in CAP.

Investigation of cytotoxicity and skin-sensitizing potential of Asarum radix oil using LLNA:BrdU-ELISA

Asarum radix extract is commonly used in cosmetic products. Cytotoxicity testing and an ex vivo local lymph node 5-bromo-2-deoxyuridine (LLNA-BrdU) assays were performed to determine the dermal sensitization potential of A. radix extracts. The cytotoxicity assay indicated inhibitory effects on cell viability in a human forearm skin fibroblast cell line after 24-h incubation at concentrations of A. radix extract above 0.075 mg/mL. To assess skin sensitization, A. radix extracts (10%, 25%, and 50% v/v) were applied to the ears (dorsal surface) of female CBA mice. Changes in clinical signs, body weight, skin reactions, ear thickness, skin stimulation index (SI), and mortality were evaluated. After 6 days, no changes in treatment-related clinical signs, skin reactions, erythema, body weight, or mortality were observed in any treatment group. The results of the ex vivo LLNA-BrdU assays yielded a moderate SI of 3.09%. For the 10%, 25%, and 50% (v/v) treatment groups, SIs were calculated as 0.9, 1.2, and 2.1, respectively. Thus, at concentrations below 25% (v/v), A. radix oil was not skin sensitizing.

Toxicological evaluation and protective effect of ethanolic leaf extract of Launaea taraxacifolia on gentamicin induced rat kidney injury

ObjectiveTo evaluate the toxic potential of Launaea taraxacifolia leaf extract (LTE) in rats within 14 d of oral administration and also assess the potential of LTE in protecting against kidney injury induced by gentamicin using rat model. MethodsThe protective ability of LTE was done after sub-acute toxicity evaluation has been carried out. Acute Kidney Injury (AKI) was induced by gentamicin at a dose of 160 mg/kg intraperitoneal i.p. Parameters and indicators considered include mortality, clinical signs, body and organ weights, haematological and clinical chemistry parameters. Gross examination and histopathological assessment was also done on selected internal organs. ResultsThere were no treatment-related deaths or changes in clinical signs, haematological and clinical chemistry indices during sub-acute toxicity studies with the exception of creatinine levels. This was confirmed by micrographs obtained from histopathological analysis. Co-administration of LTE with 160 mg/kg of gentamicin (i.p) markedly decreased the levels of urea and creatinine when compared to negative control group. Histological studies of kidney tissues showed an insignificant change in tubular epithelium in LTE plus gentamicin treated group compared to LTE treated only. ConclusionsData obtained show that ethanolic leaf extract of Launaea taraxacifolia is non-toxic within a 14 d administration at a maximum dose of 1000 mg/kg bwt and also possesses the ability to protect against gentamicin-induced kidney damage in rats at a dose of 300 mg/kg bwt.

A prospective evaluation of methylene blue and gentian violet dressing for management of chronic wounds with local infection.

The objective of this prospective, non‐randomised study was to evaluate the performance of an antibacterial foam dressing containing methylene blue and gentian violet (Hydrofera Blue Classic dressing®) for the management of chronic wounds with local infection. Patients in this study were ≥18 years of age (n = 29), and each had at least one chronic wound ≥1 cm2 in size that showed signs of localised infection or critical colonisation but with good potential for healing based on clinical assessment. To all of these wounds, the dressing was applied and changed three times per week over the 4‐week study period. The primary endpoints of the study were: (i) changes in wound surface area measurement, (ii) changes in Pressure Ulcer Scale for Healing (PUSH) scores, (iii) changes in percent surface area of devitalised tissue (i.e., yellow slough or other necrotic tissue) and (iv) changes in clinical signs associated with localised wound infection/critical colonisation. Participants were evaluated at presentation (week 0 = baseline), week 2 and at week 4 (end of the study). The 29 patients completed the study, and at week 4, the following wound improvements were observed: (i) baseline mean wound surface area was significantly reduced by 42·5%, from 21·4 to 12·3 cm2 at week 4 (P = 0·005); (ii) baseline mean PUSH score decreased significantly from 13·3 to 10·7 at week 4 (P < 0·001); (iii) baseline mean wound coverage by devitalised tissue (%) was significantly reduced, from 52·6 % to 11·4% at week 4 (P < 0·001) and (iv) the mean UPPER and LOWER wound infection scores were reduced from 3·6 at baseline to 0·9 at week 4 (75%; P < 0.001). These results indicate that the Hydrofera Blue Classic dressing was effective at managing these chronic wounds and helped them progress onto a healing trajectory.

Safety evaluation of Astragalus extract mixture HT042 and its constituent herbs in Sprague–Dawley rats

BackgroundAstragalus extract mixture HT042 is a combination of three standardized extracts from Astragalus membranaceus root, Eleutherococcus senticosus stem, and Phlomis umbrosa root, which has proven to stimulate children's height growth. PurposeThe aim of this study was to demonstrate the safety of HT042 and its three constituent herbs when administered orally. MethodsAcute and sub-chronic oral toxicity studies were conducted using male and female Sprague–Dawley rats. In the acute toxicity study, HT042 and each of the herbs was administered at single doses of up to 5000 mg/kg. In the 13-week sub-chronic toxicity study, HT042 was administered at repeated doses of up to 4000 mg/kg/day. ResultsIn the acute toxicity study of HT042 and each of the herbs, no deaths occurred and there was no indication of toxicity, on the basis of clinical signs, body weight, and necropsy findings. In the sub-chronic toxicity study of HT042, there were no deaths and no changes in clinical signs or the findings of ophthalmic examinations. Although there were some treatment-related changes in other findings, these alterations were not considered toxicologically significant because they remained within normal ranges or recovered during the recovery period. ConclusionThe oral approximate lethal doses of HT042 and each of the herbs were > 5000 mg/kg, and the no-observed-adverse-effect level of HT042 was 4000 mg/kg/day in male and female rats.

Self-perception of patients after periodontal treatment: A longitudinal study.

To investigate the perceptions of subjects regarding nonsurgical periodontal treatment over a period of 1 year. This is a secondary analysis of a randomized clinical trial, in a longitudinal observational design. Nineteen subjects (47.24 ± 6.47 years) with moderate to severe periodontitis completed a questionnaire at two different times after a nonsurgical periodontal treatment: 30 (T1) and 390 days (T2). The questionnaire with 40 items was divided into three domains: 1-perception of changes in clinical signs of periodontal disease, 2-psychological aspects of the subject regarding their oral health status, and 3-satisfaction with the treatment. Each response on the Likert scale initially showed scores ranging from 1 to 5 points. The results for each question were dichotomized into 1 or 0, respectively, showing if the subject was favorable or unfavorable to treatment. A descriptive data analysis was performed, assessing the agreement of the results in T1 and T2 (Kappa). The results generally showed a favorable perception related to the treatment and continued satisfaction over time. The exceptions were in regards to gingival recession, persistent bleeding and bad breath, and difficulty in performing the mechanical control imposed by the professional. It was concluded that the therapy used was satisfactory to the subjects and that a favorable perception was maintained after 1 year of follow-up.

The acute and sub-acute toxicity of C60/PVP complex in vivo

The detailed study of acute and sub-acute toxicity of the complex polyvinylpyrrolidon (PVP 20 kDa)-wrapped fullerene <TEX>$C_{60}$</TEX> after intraperitoneal (ip) administration was carried out on adult male Wistar rats. The <TEX>$LD_{50}$</TEX> value of <TEX>$C_{60}/PVP$</TEX> complex was found to be 7, 8 g/kg. In sub-acute study which lasted for 30 days the rats were exposed to daily administration of the complex in the doses of 350 or 700 mg/kg. All animals survived during the study and had no significant changes in clinical signs, organ weight, hematological and biochemical parameters of blood. The electrophysiological properties of myocardium and the excretory function of kidneys remained normal. Histological analysis of liver, kidney and spleen at the end of the study also did not demonstrate toxic alterations. It was thus established that intraperitoneal administration of complex <TEX>$C_{60}/PVP$</TEX> has no toxic effect. These results suggest that <TEX>$C_{60}/PVP$</TEX> has no acute and sub-acute toxicity and is a perspective substance for potential application in biology and medicine.

Сучасні підходи до лікування мастопатії у пацієнток репродуктивного віку

The aim of the study: to study the efficacy and safety of use Mastofemin in the treatment of various forms of mastitis in women of reproductive age. Materials and methods. The study included 62 women of reproductive age (mean age of 33.5±2.3 years) who were screened in the Kiev city center reproductive and perinatal medicine. Women were divided into 2 groups. The first (main) group consisted of 32 patients who received the proposed treatment using herbal remedies Mastofemin 1 capsule 2 times per day for 3 months; 30 patients of the second (control) group were under observation and received no treatment. These groups were representative and homogeneous on age, clinical symptoms and sonographic characteristics. The clinical method included evaluation of complaints of patients, anamnesis, presence of concomitant gynecologic pathology, inspection, palpation of the lymph nodes and the breast and obtaining a discharge from the nipples to conduct cytological examination, which allowed excluding from the study women with suspected malignancy of the process. All the patients were performed ultrasound examination of the breast. The review was supplemented with vaginal gynecological examination and ultrasound examination of small pelvis organs to assess the condition of the uterus and its appendages, the diagnosis of gynecological diseases. Results. Summarizing obtained in this study results one should stress the positive long-term effect of applying Mastofemin for the treatment of proliferative changes of the breast in women of reproductive age. This is manifested by a decrease in the intensity of clinical signs of mastitis, consistent with the results of sonographic control. Established positive dynamics in the treatment of cystic mastitis, dectective and when combined cystic mastopathy with dectective. In the control group of patients for a given observation period (6 months) no significant changes in clinical signs of mastitis and sonographic characteristics. Regression of disease has not occurred in any of the patients, in 2 patients increased sensitivity of the breast after 6 months moved to the soreness. Sonographic characteristics of mastitis during the observation period did not change. Thus, the use of Mastofemin aimed at pathogenetic treatment of mastitis and prevention of breast cancer. Conclusion. Application of Mastofemin during the treatment of mastitis in women of reproductive age significantly improves the clinical condition of patients; reduce the subjective and objective symptoms of the disease. The positive effect of the treatment with Mastofemin proved in the case of the treatment of sonographic following forms of mastitis: cystic mastopathy, cystic mastopathy with dectectasy. Mastofemin may be the drug of choice for complex conservative monotherapy in women of reproductive age with proliferative changes in the breast, and can also be used as part of complex treatment in patients with diffuse changes of the breast when combined with hyperplastic processes of the myometrium and endometrium. Keywords: mastopathy, breast gland, herbal medicine, herbal remedies, Mastofemin.

Safety assessment of non-animal chondroitin sulfate sodium: Subchronic study in rats, genotoxicity tests and human bioavailability

Chondroitin sulfate, an amino sugar polymer made of glucuronic acid and N-acetyl-galactosamine, is used in dietary supplements to promote joint health. Commonly used chondroitin sulfate is of animal origin and can pose potential safety problems including bovine spongiform encephalopathy (BSE). The objective of the present study was to investigate potential adverse effects, if any, of microbial derived chondroitin sulfate sodium (CSS) in subchronic toxicity, genotoxicity and bioavailability studies. In the toxicity study, Sprague Dawley rats (10/sex/group) were gavaged with CSS at dose levels of 0, 250, 500 and 1000 mg/kg body weight (bw)/day for 90-days. No mortality or significant changes in clinical signs, body weights, body weight gain or feed consumption were noted. Similarly, no toxicologically relevant treatment-related changes in hematological, clinical chemistry, urinalysis and organ weights were noted. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. In vitro mutagenic and clastogenic potentials as evaluated by Ames assay, chromosomal aberration test and micronucleus assay did not reveal genotoxicity of CSS. In pharmacokinetic study in human, CSS showed higher absorption as compared to chondroitin sulfate of animal origin. The results of subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for CSS as 1000 mg/kg bw/day, the highest dose tested.

Safety assessment of McB-E60 (extract of a Momordica sp.): Subchronic toxicity study in rats.

Momordica charantia plant is consumed as a foodstuff in some south Asian curries while its extract preparations have been traditionally used for lowering blood glucose levels in patients with diabetes mellitus. Nutritional Health Institute Laboratories (NHIL), LLC, Florida informed that it patented a new plant McB, as an interhybrid of three plants of Momordica genus. The objective of the present study was to investigate potential adverse effects, if any, of McB-E60 (extract of a Momordica sp.) in rats following subchronic administration. Sprague-Dawley rats (10/sex/group) were administered via oral gavage 0 (control), 250, 500 and 1000mg/kg body weight (bw)/day of McB-E60 for 90days. Additional 28-day recovery groups were maintained at control and high dose levels. No mortality or significant and adverse changes in clinical signs, neurological signs, body weight gain or feed intake were noted. No toxicologically significant changes in hematology, clinical chemistry, urinalysis and organ weights were noted. Gross and microscopic pathology examinations did not reveal treatment-related abnormalities. Any changes noted were incidental and within historical control ranges. Based on the results of this study, the No-Observed-Effect Level (NOEL) for McB-E60 (extract of a Momordica sp.) was determined as greater than 1000mg/kg bw/day, the highest dose tested.

Evaluation of safety of modified-Danggui Buxue Tang in rodents:immunological, toxicity and hormonal aspects

Ethnopharmacological relevanceRadix Astragali (RA), Radix Angelicae Sinensis (RAS) and Folium Epimedii (FE) are three of the extensively applied herbs among traditional Chinese medicines for gynecological disorders and osteoporosis. A derivative herbal formula—RRF, consisting of the three medicines with a weight ratio of 5:1:5, is derived from a famous Chinese herbal formula—Danggui Buxue Tang (DBT). RRF has shown noteworthy perimenopause ameliorating effect in both ovariectomized rats and natural aging female rats, which might represent a promising candidate for the treatment of perimenopausal disorders. The aim of this study was to evaluate its immunological potential, chronic toxicity and reproductive effects by 26-week repeated daily administration in female rats, in order to optimize its safe use. Materials and methodsThe effect of RRF on immunological function was studied by macrophage phagocytosis, immune organ index, serum immunoglobulin level as well as delayed type hypersensitivity (DTH) in mice. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of RRF to mice. In the oral chronic toxicity, 120 female rats were administrated RRF orally in 0, 1100, 4400, or 8800mg/kg/day doses for 26 weeks. Clinical signs, mortality, body weights, feed consumption, haemato-biochemical parameters, organ weights, histopathology and reproductive hormone profiles were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period. ResultsOral administration of RRF at three doses (282, 564 and 1128mg/kg) significantly increased the indices of phagocytosis K, as compared with prednisone acetate (PR) group (p<0.05 or 0.01). Exposure of RRF dose-dependently boosted circulating serum IgM level (all p<0.01) in response to CRBC in PR-induced mice. Furthermore, RRF treatment elicited a significant increment (all p<0.01) in DNFB-induced DTH response and the immune organ indices in a dose-dependent manner in mice, in parellel to DNFB-induced group. In the single dose acute toxicity and repeated dose 90-day chronic toxicity investigations, no toxic signs/mortality were observed. RRF treatment did not cause any toxicologically significant changes in clinical signs, food consumption, body weight, relative organ weight, hematological parameters, clinical chemistry, gross pathology and histopathology between treatment and control groups. No treatment related gross/histopathological lesions were observed and no target organ was identified. Long-term repeated administration of RRF exerted a significant promotion on serum level of steroid hormone estradiol, progesterone and testosterone release, along with decrease of circulating pituitary follicle stimulating hormone, luteinizing hormone, and prolactin levels in female rats. The No Observed Adverse Effect Level (NOAEL) of RRF was determined to be over 8800mg/kg/day for elderly female rats, a dose that was equivalent to 50 times of human dose. ConclusionThe present investigation demonstrated that RRF possessed appreciable immunopotentiating activity and had a relatively wide margin of safety. Long-term treatment of RRF exhibited estrogenic properties, and retarded certain age-associated degenerations. RRF might have the potential for further development as a safe and effective alternative/complementary to conventional medication in relieving perimenopausal symptoms.

Long-term Natural History of Dry Eye Disease from the Patient's Perspective

To describe the natural history of dry eye disease (DED), which chronically affects millions of people in the United States. This study is based on the Women's Health Study and Physicians' Health Studies, and uses questionnaires and medical records. A total of 398 men and 386 women who reported a diagnosis of DED and responded to a questionnaire about change in disease since diagnosis. Three subscales were developed using factor analysis of questionnaire responses: ocular surface symptoms, vision-related symptoms, and social impact. We examined correlates of worsening on each subscale, obtained medical records from a subset of 261 study participants, and examined changes in clinical signs of DED over time. Worsening in ocular surface symptoms, vision-related symptoms, and social impact plus clinical signs. The average duration of DED of 10.5 years (standard deviation, 9.5 years). Worsening was reported by 24% for ocular surface symptoms, 29% for vision-related symptoms, and 10% for social impact. Factors associated with worsening on at least 2 of 3 subscales included a previous report of severe DED symptoms (odds ratio [OR], 2.17 for ocular surface symptoms; OR, 2.35 for vision-related symptoms), spending >$20 per month on DED treatments (OR, 1.80 for ocular surface symptoms; OR, 1.99 for vision-related symptoms), history of blepharitis or meibomian gland dysfunction (MGD) (OR, 1.57 for vision-related symptoms; OR, 2.12 for social impact), and use of systemic beta-blockers (OR, 1.62 for ocular surface symptoms; OR, 1.84 for vision-related symptoms; OR, 1.86 for the social impact of DED). Presence of corneal staining based on review of medical records was associated with use of level 2 or higher DED treatments (OR, 1.54; confidence interval [CI], 1.01-2.36), a previous report of severe DED symptoms (OR, 1.79; CI, 1.07-3.00), having a tear break-up test performed (OR, 2.73; CI, 1.72-4.36), and having blepharitis or MGD (OR, 0.59; CI, 0.35-0.98). A proportion of patients with DED experience worsening over time, tending to report with more severe symptoms earlier in the disease. Forthcoming data on the natural history of DED from prospective studies should help clarify some of the limitations of this retrospective study.

Safety assessment of saponins extract in Dolichos falcatus Klein: Subchronic study in Sprague-Dawley rats

Ethnopharmacological relevanceDolichos falcatus Klein (DF), a Chinese Dai ethnic medicine popularly known as “Tuoyeteng” in Yunnan province of China, has been widely used in China to treat fracture, rheumatoid arthritis and soft tissue injuries for a long time. Our previous study showed that saponins in DF (DFS) ameliorated the gouty arthritis induced by MSU crystals in vivo and in vitro. The present study was carried out to evaluate the no-observed-adverse-effect level (NOAEL) of DFS. Materials and methodsSprague-Dawley rats (10/sex/group) were gavaged with DFS at dose level of 0, 50, 100 and 200mg/kg body weight /day for 90-days. ResultsDFS administration did not result in mortality or show treatment-related changes in clinical signs of toxicity, body weights gain or feed consumption. Similarly, in addition to slightly hemolytic anemia and gastrointestinal tract lesion in males of high-dose treatment group, no toxicologically significant treatment-related changes in hematological, clinical chemistry, urine analysis parameters, organ weights, and macroscopic and microscopic abnormalities were noted during the testing period. ConclusionThe results of subchronic toxicity study support the NOAEL for DFS as 200mg/kg/d in females and as 100mg/kg/d in males. These results provide an important reference for further DFS-related clinical trials or new drug exploration.

Gonado-hypophyseal lesions and reproductive hormonal changes in Brucella melitensis-infected mice and its lipopolysaccharides (LPSs)

Gonado-hypophyseal lesions and reproductive hormonal changes in Brucella melitensis-infected mice and its lipopolysaccharide (LPS) were investigated. Forty-eight mice (24 males and 24 females) were used as infection models in this study, and they were divided into three equal separate groups of eight mice based on their sex: M1, M2, and M3 and F1, F2, and F3 (M = Male, F = Female). Groups M1 and F1 were orally inoculated with sterile phosphate-buffered saline (PBS) and served as the negative control. Groups M2 and F2 were orally inoculated with 0.4 ml of 109 colony-forming units (cfu) of B. melitensis, while groups M3 and F3 were orally inoculated with 0.4 ml of LPSs from 109 cfu of B. melitensis. All the groups were observed for 10 days for changes in clinical signs or signs of mortality and then euthanized. Whole blood was collected via cardiac puncture, while tissues were fixed in 10 % formalin for histopathological processing. Histopathological lesions in the male and female reproductive tracts ranged from mild to moderate degenerative, inflammatory, and necrotic lesions. These changes were moderate in M2 than in M3 in males and in F3 than in F2 groups in females. Lesions in the pituitary gland ranged from mild to moderate inflammation and necrosis with astrogliosis. F2 and M2 groups had more lesion distribution in the pituitary gland than F3 and M3 groups. There was a 13 % decline in progesterone concentration in F2 and a 44 % decline in F3. Estradiol level declined by 33 % in F2 and slightly increased by 4.2 % in F3. Progesterone-estrogen ratio (P/E) increased by 31 % in F2 and declined by 46 % in F3. Testosterone concentration increased by 74 % in M2 and decreased by 56 % in M3. The study showed that oral administration of B. melitensis affects the pituitary gland and may alter the hypothalamic-pituitary-gonadal axis.

Dermal toxicity study of rice bran supercritical CO2 extract in Sprague-Dawley rats

The present study was carried out to evaluate the dermal toxicity of topically administered rice bran supercritical CO2 extract (RB-SCE; 500, 1,000, and 2,000 mg/kg) in male and female rats when given as a single dose and a 4-week repeated dose. In all rats that underwent the single-dose toxicity test, there were no abnormal changes in clinical signs or body weight and no deaths or abnormal gross necropsy findings related to RB-SCE. Based on the above results, the LD50 is >2,000 mg/kg in both sexes. In all rats that underwent the 4-week repeated dermal toxicity test, there were no abnormal RB-SCEassociated changes with respect to external signs, urine and blood, or organs. The no-observed-adverse-effect level (NOAEL) of RB-SCE was thus considered to be 2,000 mg/kg/day for both sexes and the target organ. RB-SCE can be regarded as a very safe agent for topical dermal administration at a moderate dose.

Dogs with separation-related problems show a “less pessimistic” cognitive bias during treatment with fluoxetine (Reconcile™) and a behaviour modification plan

BackgroundCanine separation-related problems (SRP) (also described as “separation anxiety” or “separation distress”) are among the most common behavioural complaints of dog owners. Treatment with psychoactive medication in parallel with a behaviour modification plan is well documented in the literature, but it is unknown if this is associated with an improvement in underlying affective state (emotion and mood) or simply an inhibition of the behaviour. Cognitive judgement bias tasks have been proposed as a method for assessing underlying affective state and so we used this approach to identify if any change in clinical signs during treatment was associated with a consistent change in cognitive bias (affective state).Five dogs showing signs of SRP (vocalising – e.g. barking, howling-, destruction of property, and toileting – urination or defecation- when alone) were treated with fluoxetine chewable tablets (Reconcile™) and set on a standard behaviour modification plan for two months. Questionnaires and interviews of the owners were used to monitor the clinical progress of the dogs. Subjects were also evaluated using a spatial cognitive bias test to infer changes in underlying affect prior to, and during, treatment. Concurrently, seven other dogs without signs of SRP were tested in the same way to act as controls. Furthermore, possible correlations between cognitive bias and clinical measures were also assessed for dogs with SRP.ResultsPrior to treatment, the dogs with SRP responded to ambiguous positions in the cognitive bias test negatively (i.e. with slower running speeds) compared to control dogs (p < 0.05). On weeks 2 and 6 of treatment, SRP dogs displayed similar responses in the cognitive bias test to control dogs, consistent with the possible normalization of affect during treatment, with this effect more pronounced at week 6 (p > 0.05). Questionnaire based clinical measures were significantly correlated among themselves and with performance in the cognitive bias test.ConclusionThese results demonstrate for the first time that the clinical treatment of a negative affective state and associated behaviours in a non-human species can produce a shift in cognitive bias. These findings demonstrate how the outcome of an intervention on a clinical problem can be evaluated to determine not only that the subject’s behaviour has improved, but also its psychological state (welfare)Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0373-1) contains supplementary material, which is available to authorized users.

Effect of buprenorphine on genotoxicity evaluation of chemicals by the rat liver micronucleus test with partial hepatectomy.

In the view of animal welfare considerations, we investigated the suitability of modifying the rat liver micronucleus test with partial hepatectomy to include administration of an analgesic drug to minimize pain and distress as much as possible. The effects of the analgesic, buprenorphine, on the genotoxicity evaluation of structural chromosome aberration inducers (cyclophosphamide, diethylnitrosamine and 1,2-dimethylhydrazine) and numerical chromosome aberration inducers (colchicine and carbendazim) were examined. The genotoxicants were given orally to 8-week-old male F344 rats a day before or after partial hepatectomy and hepatocytes were isolated 4 days after the partial hepatectomy. Buprenorphine was injected subcutaneously twice a day with at least a 6-hr interval for 2 days from just after partial hepatectomy. As results, buprenorphine caused neither change in clinical signs (except for one animal death) nor increase in the incidence of micronucleated hepatocytes of vehicle treated animals. In the case of concomitant treatment of buprenorphine and a genotoxicant, one out of 8 animals died in each group given buprenorphine with cyclophosphamide, carbendazim or colchicine (lower dose level only). Slight changes in clinical signs were noted in the group given buprenorphine with cyclophosphamide or carbendazim. A statistically significant increase in the incidence of micronucleated hepatocytes was obtained in concomitant treatment of buprenorphine and genotoxicant compared with genotoxicant alone for 1,2-dimethylhydrazine, colchicine and carbendazim. It is concluded that use of buprenorphine as an analgesic drug to minimize pain and distress for rats that are given partial hepatectomy is not appropriate under the present experimental conditions, because it could enhance the general toxicity and genotoxicity of the test chemical.

A 90-day study of three bruchid-resistant mung bean cultivars in Sprague-Dawley rats

Mung bean has been traditionally and widely used as an edible and medicinal plant in the South and Southeast Asia. Bruchid resistance mung bean has more potential in commercial use, but scarcely been evaluated for safety through standard in vivo toxicological studies. In the present study, subchronic oral toxicity studies of bruchid-resistant mung bean were designed and conducted in Sprague-Dawley (SD) rats for 90 days. During the subchronic oral toxicity study, no mortality and toxicologically significant changes in clinical signs, food consumption, opthalmoscopic examination, hematology, clinical biochemistry, macroscopic findings, organ weights and histopathological examination were noted in animal administered diet containing bruchid-resistant mung bean. These results demonstrated that bruchid resistant mung bean is as safe as conventional mung bean.

A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt in rats

A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt was performed in rats. Sprague-Dawley rats were randomly divided into four groups (10 rats/sex/group) and administered with PQQ disodium salt at doses of 0 (control), 100, 200 and 400 mg/kg bw/day by gavage for 13 weeks. Daily clinical observations and weekly measurement of body weights and food consumption were conducted. Blood samples were obtained on day 46 and day 91 for measurement of hematology and serum biochemical parameters. Animals were euthanized for necropsy, selected organs were weighted and recorded. Histological examination was performed on all tissues from animals in the control and PQQ disodium salt treatment groups. No mortality or toxicologically significant changes in clinical signs, body weight, food consumption, necropsy findings or organ weights was observed. Differences between treated and control groups in some hematological and serum biochemical examinations and histopathological examination were not considered treatment-related. The no-observed-adverse-effect-level (NOAEL) of PQQ disodium salt in rats was considered to be 400 mg/kg bw/day for both sexes, the highest dose tested.

Treatment effectiveness of pasireotide on health-related quality of life in patients with Cushing's disease.

Cushing's disease (CD) can significantly impair patients' health-related quality of life (HRQOL). This study investigated the treatment effectiveness of pasireotide on HRQOL of CD patients, and assessed the relationships between HRQOL and urinary free cortisol (UFC) and CD-related signs and symptoms. In this phase III, randomized, double-blind study, patients with UFC ≥1.5×upper limit of normal (ULN) received s.c. pasireotide 600 or 900 μg twice daily. The trial primary endpoint was UFC at or below ULN at month 6 without dose titration. Open-label treatment continued through month 12. HRQOL was measured using the Cushing's Quality of Life Questionnaire (CushingQoL) instrument at baseline and follow-up visits until month 12 during which clinical signs and features of CD, and the Beck Depression Inventory II (BDI-II), were also collected. Pearson's/Spearman's correlations between changes in CushingQoL and changes in clinical signs and symptoms were assessed. Changes in CushingQoL and the proportion of patients achieving a clinically meaningful improvement in CushingQoL were also compared among patients stratified by mean UFC (mUFC) control status (controlled, partially controlled, and uncontrolled) at month 6. Analyses were also conducted at month 12, with multivariable adjustment for baseline characteristics and CushingQoL. Change in CushingQoL was significantly correlated with changes in mUFC (r=-0.40), BMI (r=-0.39), weight (r=-0.41), and BDI-II (r=-0.54) at month 12 but not at month 6. The percentage of CushingQoL responders at month 12 based on month 6 mUFC control status were as follows: 63, 58.8, and 37.9% in the controlled, partially controlled, and uncontrolled groups respectively. Adjusted CushingQoL scores at month 12 were 58.3 for controlled patients (Δ=11.5 vs uncontrolled, P=0.012) and 54.5 for partially controlled patients (Δ=7.7 vs uncontrolled, P=0.170). Pasireotide treatment can result in a meaningful HRQOL improvement among those who complete a 12-month treatment period, most often among patients achieving biochemical control.