Should laparoscopic lymph node biopsy be the preferred diagnostic modality for isolated abdominal lymphadenopathy?

Background: Isolated abdominal lymphadenopathy is frequently detected, but often challenging to diagnose. To obtain a tissue diagnosis, percutaneous biopsy (pb) or laparoscopic biopsy (lb) is often undertaken. The safety profiles and diagnostic accuracy of pb and lb within the abdomen are both poorly defined. Methods: In this retrospective analysis, we identified all patients who underwent lb or pb for isolated abdominal lymphadenopathy at our institute during 2008-2016. Results: Of 62 patients who underwent nodal biopsy for isolated abdominal lymphadenopathy, 33 underwent lb and 29 underwent pb. For the 33 patients who underwent lb, the procedure was diagnostic in 100% of cases; for the 29 who underwent pb, the procedure was diagnostic in 18 cases (62.1%). Both procedures were safe, with similar complication rates (6.0% for lb; 7.0% for pb). Conclusions: Our results establish that lb and pb are both safe and reliable in the setting of isolated abdominal lymphadenopathy. We also demonstrate that each procedure has situational advantages. A pb should be considered to be the upfront diagnostic modality, particularly when anatomic or disease factors favour its success. In situations in which it is felt that pb cannot safely access the lymphadenopathy or in disease states in which the yield of a core biopsy will be insufficient, lb should be strongly considered. Examples include extra-retroperitoneal lymphadenopathy and cases of suspected lymphoma.

Equivalent dynamic human brain NK1-receptor occupancy following single-dose i.v. fosaprepitant vs. oral aprepitant as assessed by PET imaging.

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

The effects of TPA023, a GABAAα2,3 subtype-selective partial agonist, on essential tremor in comparison to alcohol.

Essential tremor (ET) is a relatively frequent neurological disorder that responds in some patients to gamma-aminobutyric acid A (GABA(A)) agonists such as the benzodiazepines. Partial subtype-selective GABA(A) agonists may have an improved side effect profile compared to non-selective GABA(A) agonists. However, it is unknown which GABA(A) subtypes are involved in the therapeutic effects of benzodiazepines in ET. The effects of 2 mg TPA023, a GABA(A) α2,3 subtype-selective partial agonist, on ET were compared to the effects of a stable alcohol level (0.6 g/L) and placebo in nine patients with ET. Tremor evaluation included laboratory accelerometry and a performance-based scale. Additional measurements were performed to evaluate other effects on the central nervous system (CNS). Alcohol significantly diminished tremor symptoms in the postural and kinetic condition, as assessed by laboratory accelerometry, but the performance-based rating scale was unaffected. Tremor was also reduced after TPA023 treatment in the kinetic condition, albeit not significantly. Additionally, TPA023 decreased saccadic peak velocity, while alcohol decreased subjective feelings of alertness. This study showed that alcohol reduced maximum tremor power, as assessed by laboratory accelerometry, unlike TPA023, which decreased tremor symptoms to some extent but not significantly. This study showed that treatment with an α2,3 subunit-selective GABA(A) partial agonist was less effective than a stable level of alcohol in reducing ET symptoms. These results provide no support for a therapeutic role of TPA023 in the suppression of ET symptoms.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist.

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Acute alertness-promoting effects of a novel histamine subtype-3 receptor inverse agonist in healthy sleep-deprived male volunteers.

The alertness-promoting effect of MK-0249 (10 or 50 mg), a histamine subtype-3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double-blind, double-dummy, placebo- and modafinil- (200 mg) controlled, four-period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK-0249 50 mg (5.17 min; P = 0.008), and MK-0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK-0249). The alertness-promoting effect with the use of MK-0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.

Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA(A) alpha2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers.

The use of non-selective gamma-aminobutyric acid (GABA) enhancers, such as benzodiazepines in the treatment of anxiety disorders is still widespread but hampered by unfavourable side effects. some of these may be associated with binding properties to certain subtypes of the GABA(A) receptor that are unnecessary for therapeutic effects. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the alpha1 subtype and significant efficacy at alpha2 and alpha3 subtypes of the GABA(A) receptor. This paper is a double-blind, four-way cross-over (n = 12) study to investigate the effects of MK-0343 (0.25 and 0.75 mg) in comparison to placebo and an anxiolytic dose (2 mg) of the non-selective agonist lorazepam. Effects were measured by eye movements, body sway, Visual Analogue scales (VAS) and memory tests. Lorazepam impaired saccadic peak velocity (SPV), VAs alertness scores, postural stability and memory and increased saccadic latency and inaccuracy. MK-0343 0.75 mg was equipotent with lorazepam as indicated by SPV (-42.4 deg/s), saccadic latency (0.02 s) and VAS alertness scores (1.50 ln mm), while effects on memory and postural stability were smaller. MK-0343 0.25 mg only affected postural stability to a similar extent as MK-0343 0.75 mg. The effect profile of MK-0343 0.75 mg is different from the full agonist lorazepam, which could reflect the selective actions of this compound. Although less effect on VAS alertness was expected, diminished effects on memory and postural stability were present. Clinical studies in anxiety patients should show whether this dose of MK-0343 is therapeutically effective with a different side-effect profile.

Carnitine, acylcarnitine and amino acid profiles analyzed by tandem mass spectrometry in a surfactant/virus mouse model of acute hepatic encephalopathy.

Tandem mass spectrometry (MS/MS) was used to analyze multiple serum metabolites for the first time in a surfactant/virus mouse model of acute hepatic encephalopathy (AHE). AHE is characterized by acute liver failure that can lead to potentially lethal increases in intracranial pressure. We have reproduced AHE in young CD-1 mice exposed from postnatal day (P) 2-13 to the industrial surfactant, Toximul 3409F (Tox), and then infected intranasally on P14 with sublethal doses (LD(10-30)) of mouse-adapted human influenza B (Lee) virus (FluB). The sera analyzed by MS/MS were from mice exhibiting typical markers of Tox-mediated potentiation of viral illness, including reduced weights and blood glucose levels. Most metabolite abnormalities were not evident until five days after viral infection (P19), the time corresponding to the onset of weight loss and mortality. Values for fatty acylcarnitines and amino acids in the Tox+FluB-treated mice were either additive or supra-additive relative to the effects of either treatment alone. Amino acid profiles were consistent with those reported for human AHE. None of the treated mice exhibited signs of carnitine deficiency, and propionylcarnitine levels were normal. On P19, mice given combined Tox+FluB treatment had significant increases in levels of both medium- and long-chain acylcarnitines (C6:0-C12:0 and C14:0-C20:0, respectively), including their monounsaturated metabolites. Levels of medium-chain dicarboxylic and long-chain hydroxy-acylcarnitines were also elevated in the combined treatment group. The results of this study indicate a diffuse mitochondrial dysfunction in Tox+FluB-treated mice that results in a serum metabolite profile unique from those observed in classic inherited metabolic disorders.

Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA(A) alpha(2,3) subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers.

TPA023, a GABA(A) alpha2,3 alphasubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the alpha1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectabLe effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABA(A) receptor subtypes.

Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women.

The alphaVbeta3 integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an alphaVbeta3 integrin antagonist, would potently inhibit bone resorption, thereby increasing bone mass as assessed by bone mineral density (BMD) in women with postmenopausal osteoporosis. In a multicenter, randomized, double-blind, placebo-controlled, 12-month study, 227 women (average 63 yr) with low lumbar spine or femoral neck BMD were randomly assigned to receive 100 or 400 mg L-000845704 once daily (qd), 200 mg L-000845704 twice daily (bid), or placebo. L-000845704 increased lumbar spine BMD (2.1, 3.1, and 3.5% for the 100-mg-qd, 400-mg-qd, and 200-mg-bid treatment groups, respectively, vs. -0.1% for placebo; P < 0.01 all treatments vs. placebo). Only 200 mg L-000845704 bid significantly increased BMD at the hip (1.7 vs. 0.3% for placebo; P < 0.03) and femoral neck (2.4 vs. 0.7% for placebo; P < 0.05). No L-000845704 group increased total body BMD. All doses of L-000845704 resulted in a similar approximately 42% decrease from baseline of N-telopeptide cross-links (P < 0.001 vs. placebo). L-000845704 was generally well tolerated; adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the antiresorptive effect of the alphaVbeta3 integrin antagonist L-000845704 translated into significant increases in lumbar spine BMD. Furthermore, 200 mg L-000845704 bid provided efficacy at the hip sites. These data suggest that the alphaVbeta3 integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.

Two formulations of the industrial surfactant, Toximul, differentially reduce mouse weight gain and hepatic glycogen in vivo during early development: effects of exposure to Influenza B Virus.

Previous studies demonstrated that young mice exposed chronically to industrial surfactant (IS) do not exhibit obvious adverse health effects, but do have persistently reduced body weights and compromised hepatic energy metabolism. The present study examined the time course of effects of two formulations of the Toximul (Tox) class of anionic/nonionic IS on body weights and liver glycogen (+/-virus) during early development. Results showed that effects differed in two commonly used strains of mice. In CFW mice, 12 days' exposure to Tox resulted in retardation of weight gain that was most obvious several days after exposure ceased. In this strain effects were greater with Tox 3409F than with Tox MP-A and appeared to be reversible except when the mice were treated with both Tox 3409F and FluB. Weights of the CD-1 mice were not affected by either Tox treatment alone, but were significantly reduced on postnatal day 20 when Tox exposure had been combined with FluB infection. Postnatal replenishment of hepatic glycogen stores during the first three weeks also occurred at different rates in CFW and CD-1 mice. The effects of Tox (+/-FluB) on glycogen also varied with mouse strain and Tox formulation. In CFW mice, exposure to either formulation resulted in significant (55-59%) reductions in glycogen, although reductions were not evident until nine days after Tox exposure stopped. By contrast, hepatic glycogen in CD-1 mice was reduced both during and after dermal exposure to Tox 3409F, whereas no effect was observed with Tox MP-A. Notably, the 3409F effect was reversible in the CD-1 mice, but reversal did not occur in mice also infected with FluB. Tox MP-A+FluB-treated mice exhibited only a transient glycogen reduction. These results illustrate the importance of mouse strain and formulation specificities in assessing biological effects of xenobiotic surfactants. As well, they emphasize that chronic IS exposure can induce changes in growth and energy substrate availability in young mice that may not be evident unless there is a precipitating cofactor such as a viral infection.

Elevated anticardiolipin antibodies in acute liver failure.

Antibodies to cardiolipin (aCLA), a phospholipid primarily localized in inner mitochondrial membranes, were transiently elevated (P<0.01) when mice were exposed to an industrial surfactant and then infected with influenza B virus, a model of acute liver failure (ALF). Children with ALF also had elevated levels of aCLA.

Evaluation of the comparative efficacy of selamectin against flea (Ctenocephalides felis felis) infestations on dogs and cats in simulated home environments.

The comparative efficacy of monthly administration of selamectin or lufenuron against Ctenocephalides felis felis on dogs and cats was evaluated over a 5-month period in flea-infested environments. Twenty-four dogs and 32 cats were randomly allocated to receiving a topical treatment with selamectin or an oral administration of tablets containing lufenuron/milbemycin oxime (for dogs) or lufenuron only (for cats). Each product was administered in accordance with the manufacturer's label recommendations. Eight dogs and four cats served as untreated sentinels. Treatments were administered on days 0, 30, 60, 90, and 120. Each animal received an application of 100 fleas on days -28 and -21, and then weekly applications of 20 fleas from days 91 through 147. Flea comb counts were performed on day -6, and every 2 weeks after day 0. From day 29 (dogs) or day 44 (cats) to day 150, geometric mean flea counts for selamectin were < or =0.4. Mean flea counts for animals assigned to treatment with selamectin were significantly lower (P=0.0001) than for animals assigned to treatment with lufenuron at all assessments after day 0.

Epidemiology of Toxascaris leonina infection post-weaning within a colony of dogs.

This communication reports incidental observations on Toxascaris leonina infections in a beagle breeding colony. Regular faecal monitoring demonstrated that T. leonina was endemic in the adult dam population within this colony. Small numbers of T. leonina eggs were also detected in the faeces of weaned pups from eight weeks of age possibly produced by a patent infection. This would mean a pre-patent period for T. leonina of 56 days or less. Worm counts on 10 pups showed that 60% of pups had acquired a T. leonina infection by 12 weeks of age. Since prenatal and lactogenic transmission do not occur and as the pups were kept in an environment which reduced chances of infection with T. leonina and there was no apparent source of paratenic hosts, the source of infection must have been embryonated T. leonina eggs from the whelping environment. These observations on T. leonina demonstrate that, if pups are exposed to an infected environment, patent infections may be seen in a younger age group than is normally associated with T. leonina infections.

The effects of rhBMP-2 on human osteosarcoma cells and human gingival fibroblasts in vitro.

Certain cells of the periodontium are necessary for the regeneration of tissues that are destroyed as a result of periodontal disease. There has been debate regarding which cells are the primary participants in periodontal regeneration. It is a well-known fact that osteoblasts are essential in new bone formation, but controversy surrounds the role that gingival fibroblasts may play in the regeneration of the hard tissues of the periodontium. If gingival fibroblasts could contribute to the regeneration of these tissues, they might provide an additional source of progenitor cells. The bone morphogenetic proteins are potent stimulators of cell differentiation and have been shown to induce new bone formation in many experimental models. This project investigated the ability of recombinant human bone morphogenetic protein-2 (rhBMP-2) to (1) enhance the production of markers of osteoblastlike cells (osteocalcin and mineralization in culture) in human osteosarcoma cells (MG63) and to (2) induce the expression of an osteoblast phenotype in cultured human gingival fibroblasts (HGFs). MG63 cells and pooled HGFs were exposed to varying concentrations of rhBMP-2 for 24, 48, and 72 hours after 9 days in culture, and osteocalcin levels were measured by enzyme immunosorbent assay in the cell supernatants. In addition, the cells were exposed to rhBMP-2 for 72 hours after 18 days in culture, and mineralization was determined by the Von Kossa stain. The rhBMP-2 had an inhibitory effect on both osteocalcin production and mineralization (p < 0.05) in MG63 cells compared with untreated controls. In addition, increasing doses of rhBMP-2 inhibited both osteocalcin and mineralization in HGF cells. These results suggest that HGFs can express an osteoblastic phenotype when exposed to rhBMP-2; however, rhBMP-2 has inhibitory effects at higher rhBMP-2 doses in both cell types and may, in fact, be inhibitory to MG63 cells.

Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women.

GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.

Efficacy of selamectin against adult flea infestations (Ctenocephalides felis felis and Ctenocephalides canis) on dogs and cats.

Selamectin was evaluated in eight controlled studies (4 in dogs, 4 in cats) to determine the efficacy of a single topical unit dose providing the recommended minimum dosage of 6mgkg(-1) against Ctenocephalides felis felis and Ctenocephalides canis fleas on dogs and against C. felis on cats. In addition, the effect of bathing on the efficacy of selamectin against C. felis was evaluated. Identical studies were performed in Beagles and domestic shorthaired cats. For each study, animals were allocated randomly to treatments of 8-12 animals each. All studies (dog studies A, B, C, and D and cat studies A, B, C, and D) evaluated the efficacy of selamectin without bathing. In addition, study C in both dogs and cats evaluated efficacy with a shampoo bath at 24h after dosing, and study D evaluated the efficacy of selamectin with water soaking at 2h after dosing or with a shampoo bath at 2-6h after dosing. Dog study B evaluated efficacy against C. canis, whereas all other studies used C. felis. In each study, selamectin was administered on day 0 as a topical dose that was applied directly to the skin in a single spot at the base of the neck in front of the scapulae. Dogs and cats were infested with approximately 100 viable unfed C. felis or C. canis on days 4, 11, 18, and 27. On days 7, 14, 21, and 30, approximately 72h after infestation, a comb count of the number of viable fleas present on each animal was made. For C. felis and C. canis for dogs and cats, compared with controls, selamectin achieved significant reductions in geometric mean adult flea comb counts of > or =98.9% on days 7, 14, and 21 in all eight studies. On day 30, the reduction for C. felis remained at or above 98.0%. This included the dogs and cats that were soaked with water or bathed with shampoo at 2, 6, or 24h after treatment. There were no significant (P>0.05) differences between the flea counts from selamectin-treated animals in these studies, regardless of bathing status. On day 30, a significant reduction of 91.8% was achieved against C. canis on dogs. Thus, these studies demonstrated that a single topical unit dose of selamectin was highly effective against adult fleas on dogs and cats for at least 27 days.

Evaluation of the effects of selamectin against adult and immature stages of fleas (Ctenocephalides felis felis) on dogs and cats.

The adulticidal, ovicidal, and larvicidal effects of selamectin against flea (Ctenocephalides felis felis) infestations on dogs and cats were evaluated in a series of seven controlled and masked studies (three in cats, four in dogs). Animals were randomly allocated to treatment with either selamectin at a minimum dosage of 6mgkg(-1) in the commercial formulation or one of two negative-controls (0.9% NaCl solution or the vehicle from the commercial formulation). Treatments were administered topically in a single spot on the skin at the base of the neck in front of the scapulae. Speed of kill, measured by flea comb counts at 12h intervals during the 48h immediately following a single treatment on day 0, was evaluated in two studies. One study was in dogs and the other in cats, and each animal was infested with approximately 100 unfed viable adult fleas prior to treatment. Reductions in geometric mean flea counts for selamectin compared with saline were >98% between 24 and 36h after treatment in dogs, and between 12 and 24h after treatment in cats (P< or =0.0006). Efficacy in reducing flea egg hatch and larval development was evaluated in four studies, in which dogs and cats were treated once on day 0 and then repeatedly infested with approximately 600 fleas. Flea eggs were collected approximately for 72h after each infestation, on days 3, 7, 14, 21, and 30, counted, and cultured to determine their hatchability and subsequent larval development. Compared with the vehicle, selamectin was highly effective in reducing flea egg hatch (>92% in cats) and larval development (> or =95% for dogs and cats), and emergence of adults (97.8-100% for dogs, 85.6-100% for cats) for 30 days. Effects of exposure to hair coat debris were investigated in a study with dogs treated once on day 0 and repeatedly infested with 100 adult fleas. Debris (dander, flea faeces, hair, scales) was collected on days 1, 7, 14, 21, and 30 and added to normal flea eggs or larvae for incubation. Compared with debris from vehicle-treated dogs, debris from selamectin-treated dogs was highly effective in preventing egg hatch (>96%), in killing larvae (>98%) and in preventing larval development to adults (>99%) (P

Efficacy of selamectin in the treatment and prevention of flea (Ctenocephalides felis felis) infestations on dogs and cats housed in simulated home environments.

The efficacy of selamectin, a novel avermectin, in protecting dogs and cats against experimentally induced environmental flea (Ctenocephalides felis felis) infestations, was evaluated in a series of controlled and masked studies. Purpose-bred shorthaired cats and Beagles were randomly allocated to treatment with either selamectin at a minimum dosage of 6mgkg(-1) of body weight in the commercial formulation or the negative control treatment (vehicle only), and housed in controlled simulated home environments capable of supporting the flea life cycle. Day 0 was defined as the first day of treatment. Treatments were administered topically in a single spot on the skin at the base of the neck in front of the scapulae. In environmental challenge studies, which were designed to evaluate the efficacy of selamectin in the treatment and control of established flea infestations, dogs and cats were each infested with 100 fleas on days -28 and -21 and placed in carpeted rooms in order to establish high levels of active flea infestation prior to day 0. Treatments were administered monthly for 3 months. Flea comb counts were performed on days 14, 29, 44, 59, 74, and 90. Reductions in geometric mean flea comb counts for selamectin, compared with vehicle, were >99% from day 14 onwards for dogs, and >92% on day 29 and >99% on days 44, 59, 74, and 90 for cats (P=0.0001). In prevention of environmental infestation studies, dogs and cats were placed in environments capable of supporting flea infestations and given monthly treatments for 2 months, commencing on day 0. Animals were infested with 100 fleas on days 1 and 7, and flea comb counts were performed on days 29, 44, and 60. Reductions in geometric mean flea comb counts for selamectin, compared with vehicle, were >99% on days 29, 44, and 60 (P=0.0001) for dogs and cats. Monthly administration of selamectin to dogs and cats housed in environments highly suited to completion of the flea life cycle was shown to be highly effective in the treatment and prevention of flea infestations, without the need for supplementary environmental control measures.