Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma

Background

Idarubicin, a PO bioavailable anthracycline antibiotic‐class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery.

Objectives

The primary objective of this study was to determine the maximally tolerated dose (MTD), dose‐limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD.

Animals

Client‐owned dogs with measurable lymphoma.

Methods

Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines.

Results

The MTD in dogs > 15 kg body weight was 22 mg/m². Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol.

Conclusions and Clinical Importance

PO administered idarubicin was generally well‐tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated‐dose, randomized clinical trials.     

Circulating cytokine concentrations in dogs with different degrees of myxomatous mitral valve disease

Cytokines have been associated with the progression of congestive heart failure (CHF) in humans and may be implicated in the pathophysiology of myxomatous mitral valve disease (MMVD) in dogs. The aim of this study was to determine the serum concentrations of cytokines in dogs with MMVD. The study included 16 Cairn terriers with no or minimal mitral regurgitation (MR), 41 Cavalier King Charles Spaniels (CKCS) with different degrees of MR and 11 dogs of different breeds with CHF due to MMVD. Granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, keratinocyte-derived chemokine, interferon-γ-induced protein and monocyte chemoattractant protein-1 (MCP-1) were measured using a canine-specific multiplex immunoassay. CHF dogs had significantly higher MCP-1 concentrations than dogs with no or minimal MR. Among the CKCS, IL-2 and IL-7 decreased with increasing left atrial size and IL-7 also decreased with increasing MR. IL-8 decreased with increasing left ventricular end-systolic internal dimensions. MCP-1 was increased in CHF dogs compared to healthy control dogs and IL-2, IL-7 and IL-8 decreased with increasing indices of disease severity. The results suggest a role for these cytokines in canine MMVD and CHF.     

Nematicidal activity of plant essential oils and components from coriander (Coriandrum sativum), Oriental sweetgum (Liquidambar orientalis), and valerian (Valeriana wallichii) essential oils against pine wood nematode (Bursaphelenchus xylophilus)

Commercial essential oils from 28 plant species were tested for their nematicidal activities against the pine wood nematode, Bursaphelenchus xylophilus. Good nematicidal activity against B. xylophilus was achieved with essential oils of coriander (Coriandrum sativum), Oriental sweetgum (Liquidambar orientalis), and valerian (Valeriana wallichii). Analysis by gas chromatography-mass spectrometry led to the identification of 26, 11, and 4 major compounds from coriander (Coriandrum sativum), Oriental sweetgum (Liquidambar orientalis), and valerian (Valeriana wallichii) oils, respectively. Compounds from each plant essential oil were tested individually for their nematicidal activities against the pine wood nematode. Among the compounds, benzaldehyde, trans-cinnamyl alcohol, cis-asarone, octanal, nonanal, decanal, trans-2-decenal, undecanal, dodecanal, decanol, and trans-2-decen-1-ol showed strong nematicidal activity. The essential oils described herein merit further study as potential nematicides against the pine wood nematode.     

The genetic organisation of the capsule biosynthesis region of Actinobacillus pleuropneumoniae serotypes 1, 6, 7, and 12

The aim of the present study was to investigate the organisation of the genes (cps) involved in biosynthesis the capsular polysaccharide (CPS) of Actinobacillus pleuropneumoniae serotypes 6, 7, and 12 and to compare these to the corresponding genes previously described in other A. pleuropneumoniae serotypes. In serotypes 6 and 7 the sequenced DNA regions comprised five and four open reading frames, respectively, designated cps6ABCDE and cps7ABCD, whereas the sequenced DNA region in serotype 12 comprised only two open reading frames designated cps12AB. At the amino acid level, CpsA, CpsB, and CpsC of A. pleuropneumoniae serotypes 2, 6, 7, and 8 contained a high degree of homology. At the amino acid level Cps6D revealed a high degree of homology to Cps8D, whereas Cps7D contained a high degree of homology to the Cps2D. The deduced gene product of the partially sequenced cps6E gene showed no homology to any deduced gene products of any cps genes of A. pleuropneumoniae investigated so far. None of the deduced gene products of the cps genes involved in encapsulation of A. pleuropneumoniae serotypes 2, 6, 7, and 8 revealed homology to the deduced gene products of the cps genes of serotypes 1, 5A, and 12. For some genes, a local homology was found to genes probably involved in teichoic acid synthesis in other bacteria. The results obtained revealed a high degree of homology among the genes involved in CPS biosynthesis for serotypes 2, 6, 7, and 8 and a different group of homologous cps genes for serotypes 1 and 12. In some serotype 7 strains, including the serotype 7 reference strain, WF83, the cps genes were not located adjacent to the genes responsible for CPS export (cpx), probably due to genetic rearrangements.     

A survey to determine the presence and distribution of largemouth bass virus in wild freshwater bass in New York State

During 2004 and 2005 a survey was conducted to investigate the presence and geographic distribution of largemouth bass virus (LMBV) in New York State. This iridovirus is widely distributed across the eastern United States; however, it had not previously been reported in New York State. Two hundred and eighty-three wild largemouth bass Micropterus salmoides and 8 smallmouth bass M. dolomieu were collected from 37 locations across the state. No clinical signs of LMBV or mortalities attributable to the virus were observed in the fish collected. Using a quantitative polymerase chain reaction (QPCR) method, we detected LMBV in 28 fish from 13 locations. Viral cytopathic effect in cell culture was observed in 5 fish from 3 locations. The virus isolated from cell culture was confirmed to be LMBV by an independent PCR method. Statistical analysis of the largemouth bass samples collected during 2005 revealed a wide difference in prevalence between the QPCR results and the cell culture results. Analysis of possible predictors, including age, sex, and month collected, showed no significant associations with the QPCR results. This survey confirms the presence and wide distribution of a potentially pathogenic form of LMBV in multiple water systems across New York State.     

The absorption, tissue distribution and excretion of enteraly administered alpha-ketoglutarate in rats

The absorption, tissue distribution and excretion of enteral alpha-ketoglutarate (AKG) was studied in four experiments. Six male Sprague Dawley rats were used to investigate the excretion of AKG in urine and faeces. Thirty rats, randomly assigned to five groups, were used to investigate the distribution of AKG in body tissues. They were gavaged with AKG enriched with 3 muCi/kg BW of (14)C uniformly marked AKG. Fourteen male Sprague Dawley rats were used to study the absorption of AKG (duodenum vs. ileum). Intestinal recovery of NaAKG vs. CaAKG was investigated in 36 rats. There was no significant excretion of non-metabolized AKG in the urine and faeces. There was no significant difference in the systemic levels of AKG when comparing the proximal to distal small intestine infusion. Up to 50%, 30% and 20% of gastrically delivered AKG was recovered in the stomach, 0.5, 1 and 2 h after gavage; the jejunal recovery achieved a maximum of 3%, 30 min after gavage, and was not detectable 2 h later. There was a relatively high distribution of (14)C-AKG in the tissues (e.g. liver, brain, bones, skin, muscles), 3 h after gavage, up to 70% of the administered dose. In conclusion, the high rate of retention of the carbon from AKG allows the postulation that there is a non-energetic mode of metabolism of intragastrically administered AKG. After conversion to final metabolites, AKG penetrates into all tissues and organs of rats, including the bone tissue. Intestinal absorption of AKG does not depend on the type of AKG salt administered.     

Simulating the spread of classical swine fever virus between a hypothetical wild-boar population and domestic pig herds in Denmark

Denmark has no free-range wild-boar population. However, Danish wildlife organizations have suggested that wild boar should be reintroduced into the wild to broaden national biodiversity. Danish pig farmers fear that this would lead to a higher risk of introduction of classical swine fever virus (CSFV), which could have enormous consequences in terms of loss of pork exports. We conducted a risk assessment to address the additional risk of introducing and spreading CSFV due to the reintroduction of wild boar. In this paper, we present the part of the risk assessment that deals with the spread of CSFV between the hypothetical wild-boar population and the domestic population. Furthermore, the economic impact is assessed taking the perspective of the Danish national budget and the Danish pig industry. We used InterSpreadPlus to model the differential classical swine fever (CSF) risk due to wild boar. Nine scenarios were run to elucidate the effect of: (a) presence of wild boar (yes/no), (b) locations for the index case (domestic pig herd/wild-boar group), (c) type of control strategy for wild boar (hunting/vaccination) and (d) presence of free-range domestic pigs. The presence of free-range wild boar was simulated in two large forests using data from wildlife studies and Danish habitat data. For each scenario, we estimated (1) the control costs borne by the veterinary authorities, (2) the control-related costs to farmers and (3) the loss of exports associated with an epidemic. Our simulations predict that CSFV will be transmitted from the domestic pig population to wild boar if the infected domestic pig herd is located close to an area with wild boar (<5 km). If an outbreak begins in the wild-boar population, the epidemic will last longer and will occasionally lead to several epidemics because of periodic transfer of virus from groups of infected wild boar to domestic pig herds. The size and duration of the epidemic will be reduced if there are no free-range domestic pig herds in the area with CSF-infected wild boar. The economic calculations showed that the total national costs for Denmark (i.e. the direct costs to the national budget and the costs to the pig industry) related to an outbreak of CSF in Denmark will be highly driven by the reactions of the export markets and in particular of the non-EU markets. Unfortunately, there is a substantial amount of uncertainty surrounding this issue. If hunting is used as a control measure, the average expenses related to a CSF outbreak will be 40% higher if wild boar are present compared with not present. However, a vaccination strategy for wild boar will double the total costs compared with a hunting strategy.     

Development of a composite orthopaedic pain scale in horses

This study addresses development and validation of a composite multifactorial pain scale (CPS) in an experimental equine model of acute orthopaedic pain. Eighteen horses were allocated to control (sedation with/without epidural analgesia - mixture of morphine, ropivacaine, detomidine and ketamine) and experimental groups: amphotericin-B injection in the tarsocrural joint induced pain and analgesia was either i.v. phenylbutazone administered post-induction of synovitis, or pre-emptive epidural mixture, or a pre-emptive combination of the 2. Inter- and intra-observer reproducibility was good (0.8相似文献   

The effect of dietary copper supplementation on fatty acid profile and oxidative stability of adipose depots in Boer x Spanish goats

A feeding trial was designed to examine the effects of copper sulfate pentahydrate (CuSO(4).5H(2)O) on the fatty acid composition and oxidative stability in muscle and adipose tissues of Boer x Spanish goat kids. Fifteen (n = 5 per treatment) goats were fed 0, 100, or 200 mg of supplemental Cu per day as copper sulfate for 98 d. The animals were slaughtered, and LM, s.c. adipose from the sternal region, and mesenteric adipose tissues were collected. Total lipids were extracted with chloroform:methanol (2:1), methylated and isolated via GLC from all tissues. The subsequent peaks were then positively identified by mass spectrometry. Thiobarbituric acid-reactive substances were measured also. In s.c. adipose, dietary Cu significantly decreased C14:0 (P = 0.03) and C16:0 (P = 0.01). In muscle, C15:0 (P = 0.03) was linearly increased by Cu. Dietary Cu supplementation did not influence oxidative stability in goat muscle or s.c. adipose. Copper supplementation at 200 mg/d resulted in a significant increase in malondialdehyde in mesenteric adipose (P = 0.01) compared with the 0 or 100 mg/d groups. These results indicate that lipid composition may differ from depot to depot and that depending on the depot, dietary Cu seems to elicit a variable response on the fatty acid composition.