Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication.

PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC50 for PF614 was ≥300 µM. PF614 (0.1 and 10 µM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.

Severe Sub-Acromial Bursitis with Rice Bodies in a Patient with Rheumatoid Arthritis: A Case Report and Review of Literature.

Multiple rice body formation is a rare presentation of chronic sub-acromial bursitis secondary to extensive underlying rheumatoid arthritis, sero-negative inflammatory arthritis or tuberculous joints. Although there is usually an accompanying inflammatory arthropathy, it can occur in the absence of any underlying systemic disorder. We report a case of five years old neglected rice body deposition in shoulder in a 54-years old lady diagnosed to be having rheumatoid arthritis. After initial investigations, arthroscopic removal of rice bodies with bursa excision relieved the symptoms. The underlying rheumatic condition continued its course, generally sparing the involved shoulder joint. We suggest thorough examination for systemic rheumatologic disease in patients diagnosed with such lesions.

2-Deoxy-d-Glucose (2-DG)-Induced Cardiac Toxicity in Rat: NT-proBNP and BNP as Potential Early Cardiac Safety Biomarkers.

2-Deoxy-d-glucose (2-DG) is being developed as a potential anticonvulsant and disease-modifying agent for patients with epilepsy; however, during preclinical development, cardiac toxicity has been encountered in rats. This study was performed to determine whether cardiac troponin (cTnI and cTnT), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and/or creatine kinase (CK) could be useful as indicators of 2-DG cardiac toxicity. In addition, this study also investigated the association of cardiac histopathological changes with these biomarkers. F344 rats (4/sex/group/sacrifice point) were gavaged with either vehicle or 2-DG (50, 125, or 375 mg/kg twice daily; total daily dose of 100, 250, or 750 mg/kg/d) for 7, 14, 21, or 45 days followed by a 15-day recovery. Dose-dependent increases in NT-proBNP and BNP plasma concentrations were observed. Following recovery period, the NT-proBNP and BNP concentrations returned to baseline levels. There were no remarkable increases in CK, ANP, cTnI, or cTnT concentrations. There were no gross cardiac lesions observed at the necropsy. Microscopic findings of vacuolar degeneration and hypertrophy of the endothelial cells of the endocardium were present in the heart at doses of 250 and 750 mg/kg/d. Microscopic findings, in general, were associated with increases in NT-proBNP levels. Cardiac toxicity appeared to be reversible. In conclusion, NT-proBNP and BNP are potential early biomarkers for 2-DG-induced cardiac toxicity that can be useful to monitor 2-DG therapy in clinical trials.

Conception rates to artificial insemination in primiparous, suckled cows exposed to the biostimulatory effect of bulls before and during a gonadotropin-releasing hormone-based estrus synchronization protocol.

The objective of these studies was to evaluate whether exposing primiparous, suckled beef cows to the biostimulatory effect of bulls alters breeding performance associated with an estrus synchronization protocol that included GnRH followed 7 d later by PGF(2alpha) and fixed-time AI (TAI). This was a composite analysis of 3 experiments that evaluated (1) the effects of bull exposure at different days after calving (yr 1); (2) the biostimulatory effects of bull excretory products (yr 2); and (3) the biostimulatory effects of familiar and unfamiliar bulls (yr 3) on the resumption of ovarian cycling activity. In all studies, cows were exposed (biostimulated; n = 94) or not exposed (nonbiostimulated; n = 67) to bulls or excretory products of bulls for at least 60 d before the beginning of the estrus synchronization protocol. Average calving day did not differ among years and was 52 +/- 5 d. Year did not affect the proportions of biostimulated and nonbiostimulated cows that were cycling at the beginning of the estrus synchronization protocol; however, a greater (P < 0.001) proportion of biostimulated than nonbiostimulated cows were cycling at this time. In each year, cows were given GnRH followed by PGF(2alpha) 7 d later. Cows were observed for estrus twice daily (am and pm) after PGF(2alpha). Cows that exhibited estrus before 54, 60, and 64 h after PGF(2alpha) were inseminated by AI 12 h later in yr 1, 2, and 3, respectively. Cows that failed to show estrus were given GnRH and TAI at 62, 72, and 72 h after PGF(2alpha) in yr 1, 2, and 3, respectively. Conception rates were determined by transrectal ultrasonography 35 d after TAI in each year. The percentages of cows that exhibited estrus after PGF(2alpha) and before TAI, the interval from PGF(2alpha) to estrus, and the percentages of cows inseminated 12 h after estrus or at TAI did not differ between biostimulated and nonbiostimulated cows and were 51%, 54.7 +/- 7.3 h, 35%, and 65%, respectively. Conception rates for cows bred by AI 12 h after estrus did not differ between biostimulated and nonbiostimulated cows; however, the TAI conception rate was greater (P < 0.05) for biostimulated cows (57.6%) than for nonbiostimulated cows (35.6%). We conclude that TAI conception rates in an estrus synchronization protocol that includes GnRH followed 7 d later by PGF(2alpha) may be improved by the biostimulatory effect of bulls in postpartum, primiparous cows.

Postpartum resumption of ovarian cycling activity in first-calf suckled beef cows exposed to familiar or unfamiliar bulls.

The objective of this experiment was to determine if the proportion of first-calf suckled beef cows that resumed ovulatory cycles and the interval to resumption of ovarian cycling activity differ after exposure to either "unfamiliar" bulls or cows on d 35 postpartum, after exposure to either "familiar" bulls or cows for the first 30-32 d after calving. Fifty AngusxHereford cows were stratified by calving date, calf BW, and calf sex by d 3 postpartum, and assigned to be exposed to familiar epididectomized bulls (BEF; n=25) or familiar mature ovariectomized (OVX) cows (CEF; n=25). On d 35 after calving, 12 BEF cows were assigned to be exposed to unfamiliar bulls (BEU); likewise, 12 CEF cows were assigned to be exposed to unfamiliar OVX cows (CEU). Cows were in their treatments for either 95 d (BEF and CEF) or 60 d (BEU and CEU) during the experiment. Blood samples were collected every third d from the beginning to the end of the experiment. A rise in progesterone concentration of >0.5ng/mL in consecutive samples was used as the criterion for resumption of ovulatory cycles. Exposing cows to bulls on d 5 after calving and then switching a subset of these cows to be exposed to unfamiliar bulls 30-32 d later did not (P>0.10) alter: (1) the proportion of cows that resumed cycling activity; and (2) postpartum interval to resumption of ovarian cycling activity compared to cows exposed to familiar bulls. However, 32% more (P<0.05) cows exposed to bulls (BEF and BEU) resumed cycling activity by approximately 14.8 d before cows that were exposed to OVX cows (CEF and CEU). We conclude that the familiarity of first-calf cows to either bulls or ovariectomized cows, did not affect the postpartum occurrence of cycling activity or the interval from calving to resumption of ovulatory cycles. However, bull exposure, whether familiar or unfamiliar, stimulates first-calf cows to resume ovulatory cycles sooner after calving than if they are not exposed to bulls.

Initiation of postpartum luteal function in primiparous restricted-suckled beef cows exposed to a bull or excretory products of bulls or cows.

The objective of this study was to evaluate the influence of bull excretory products on the resumption of postpartum luteal function in primiparous, restricted-suckled cows. Hypotheses tested were that resumption of luteal function or proportions of cows that initiate luteal cycling did not differ among cows exposed to a bull (BE), exposed to excretory products of bulls (EPB), not exposed to a bull (NE), or exposed to excretory products of cows (EPC). Two-year-old Angus x Hereford cows were assigned 35 d after calving to one of the four treatments (n = 15, 16, 16, and 15 for BE, EPB, NE, and EPC, respectively). Cows in the EPB and EPC treatments were placed in enclosures for 10 to 12 h, between 1830 and 0800 daily. Each enclosure was occupied by bulls (EPB) or left empty (EPC) for 10 to 12 h (0800 to 1830) daily. All cows were restricted to suckling twice daily (0800 and 1800) beginning on d 0. Blood samples were obtained from each cow on d -1 and every third day of the study thereafter. An increase in progesterone concentrations in three consecutive samples that exceeded 1.0 ng/mL was used as evidence of resumption of luteal function. Interval from d 0 to resumption of luteal activity was less for (P < 0.05) BE and EPB cows than for NE cows, but did not differ between BE and EPB cows. Interval for EPC cows did not differ from that for NE cows; however, interval for EPC cows was greater (P = 0.06) than that for BE cows and was longer (P < 0.05) than that of EPB cows. Proportions of cows that resumed luteal function by d 40 and 50 did not differ between NE and EPC cows; however, proportions of EPB and BE cows that resumed luteal function were greater (P < 0.05) than those for NE and EPC cows by d 40 and 50. Proportions of cows that resumed luteal function by d 70 were greater (P < 0.05) for BE, EPB, and EPC cows than for NE cows; however, proportions of BE and EPC cows did not differ. The proportion of EPB cows that resumed luteal function was greater (P = 0.058) than that of EPC cows, but the proportion of BE cows that resumed luteal function did not differ from that of EPC cows by d 70. We conclude that exposing primiparous restricted-suckled cows to excretory products of bulls or crowding estrus-cycling cows in an enclosure hastened postpartum resumption of luteal function. Therefore, the biostimulatory role of bulls and the crowding effect of cows seem to be mediated by a pheromone (or pheremones) present in their excretory products.

Introduction of bulls at different days postpartum on resumption of ovarian cycling activity in primiparous beef cows.

The objective of this study was to evaluate postpartum resumption of ovulatory cycles among primiparous, suckled beef cows that were exposed continuously to mature bulls beginning at various intervals after calving. We sought to determine whether cumulative distributions of proportions of cows resuming ovarian cycles and interval from the start of bull exposure to resumption of ovarian cycling activity differed among cows exposed continuously (BE) or not exposed (NE) to bulls beginning on d 15, 35, or 55 after calving. Angus x Hereford cows (n = 56) were assigned randomly to one of six treatments in a 2 (exposure type) x 3 (day exposed postpartum) factorial arrangement. Blood samples were collected from each cow starting on d -1, and every third day until the end of experiment. An increase in baseline progesterone concentrations that exceeded 1.0 ng/mL in three consecutive samples was used as evidence of resumption of ovarian cycling activity. More (P < 0.05) BE cows resumed cycling activity by the end of the experiment than NE cows. Proportions of cows resuming cycling activity did not differ (P = 0.30) among cows exposed to bulls on d 15, 35, or 55 postpartum. Proportions of BE cows that were exposed to bulls on d 15, 35, or 55 were greater for each 10-d interval (P < 0.05) than those for NE cows during the first 40 d after exposure. More (P < 0.05) BE cows exposed to bulls on d 55 resumed cycling activity by 30 d after exposure than BE cows exposed to bulls on either d 15 or 35. Interval from calving to resumption of cycling activity was decreased (P < 0.05) by the presence of bulls. Day of exposure did not affect (P = 0.21) interval from calving to resumption of cycling activity; however, interval from day of bull exposure to resumption of cycling activity decreased (P < 0.05) linearly as day of exposure to bulls after calving increased. We conclude that exposing primiparous beef cows to bulls decreased the postpartum anovulatory interval and increased the proportion of cows that exhibit resumption of ovarian cycling activity, independent of day of bull exposure. Furthermore, cows exposed to bulls at progressively later intervals postpartum seemed to respond more rapidly to the biostimulatory effect of bulls than when they were exposed earlier in the postpartum anestrous period.

Role of high speed biopsy gun in breast cancer diagnosis.

Preoperative diagnosis of histology and receptor status is important in management of breast cancer. Percutaneous automated core biopsy with biopsy gun (Gun biopsy) was done in fifty patients with palpable breast lump in whom fine needle aspiration cytology (FNAC) was either negative or not done In all patients adequate tissue for histology and receptor status studies was obtained forty-two patients had infiltrating duct carcinoma and eight patients had benign lesions on gun biopsy. There were no complications in this procedure. Twenty of the forty-two patients underwent mastectomy either per primum or after chemotherapy, had the diagnosis substantiated on histopathological examination Thirty-four samples were examined for receptor status and the specimen was found to be adequate and of good quality. We conclude that gun biopsy is a simple and safe procedure which is more sensitive and specific than FNAC.

Acute neoplastic arterial embolism after pneumonectomy.

Intra-arterial tumour embolism after pneumonectomy is a known but rare complication. It arises because of tumour involvement of pulmonary veins. Usual outcome of this complication is grave when embolism is to a major vessel. If embolism occurs in a peripheral circulation, timely intervention can avoid significant morbidity. We report a case where embolisation occurred in both the femoral arteries. Emergency embolectomy was done successfully avoiding major complication.

The mechanism of action of aspirin--is there anything beyond cyclo-oxygenase?

Aspirin, today, is an established drug in the regime for the prevention of myocardial infarction, especially in high-risk groups. This use of aspirin has given it a new lease of life in its tenth decade of clinical use. Aspirin is probably the oldest synthetic drug in the Pharmacopoeias today; thus one would have imagined that understanding about the drug would have reached a zenith and if not, that at least there should be certainty about its mechanism of action. Most workers agree that aspirin inhibits the cyclo-oxygenase enzyme in the platelets leading to reduced formation of prostaglandin G2, the precursor of thromboxanes. This explanation does not appear to be complete, since the role of the platelet activating factor (PAF) seems to have been ignored. The precursor for PAF is the lysophospholipid that is almost always formed when membrane phospholipid breakdown takes place. Any effective antiplatelet drug would have to inhibit the formation and/or the action of PAF, if it were to prevent platelet aggregation. Alternatively, the pathophysiological role attributed to PAF is highly exaggerated and needs to be reassessed.

Effect of vitamin A nutritional status on the growth of oestrogen-primed chick oviduct.

Growth and development of the oestrogen-primed oviduct of immature chicks in terms of weight, length, total protein, total RNA, total DNA and total phospholipids are markedly arrested on deprivation of vitamin A; supplementation with retinyl acetate reversed the effect of the deficiency almost fully, whereas retinoic acid was only partly effective.

Vitamin A economy of the developing chick embryo and of the freshly hatched chick.

1. The changes in the net amounts of retinol, retinyl esters and retinal in both the developing chick embryo and the newly hatched chick were investigated. The embryo requires about 68nmol of the vitamin for its growth, whereas the baby chick requires about 108nmol during the first 7 days after hatching. 2. Retinal was present in the egg in fairly high concentrations at the beginning of the incubation but it virtually disappeared from the extra-embryonic tissue after day 17 of incubation. It was not found in the liver of the embryo or of the newly hatched chick up until day 7.