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Subcutaneous injections of the tachykinin senktide reduce alcohol intake in alcohol-preferring rats.

The present study evaluated the effect of SC injections of the selective NK3 tachykinin agonist, Suc-[Asp6,MePhe8]substance P(6-11), also referred to as senktide (SENK), on 8% alcohol intake in genetically selected alcohol-preferring rats. Animals were offered access to 8% ethanol for 2 h/day (between 1800 and 2000 h) and to tap water for 4 h/day (between 1800 and 2200 h); SENK was injected 10 min before access to fluids. The peptide significantly reduced alcohol intake at doses of 125 and 250 micrograms/kg, but not at 62.5 micrograms/kg. The reduction in alcohol intake was accompanied by a sharp increase in water intake, so that total fluid intake was never significantly modified. The same SC doses of SENK did not modify water intake in rats with access to water, as the only fluid, for 4 h/day. In food-deprived rats food intake was not altered by 125 micrograms/kg, whereas 250 micrograms/kg produced a reduction in food intake that was smaller in intensity and shorter lasting than the reduction in alcohol intake. The same doses of SENK did not modify 0.1% saccharin intake, nor did they elicit major competing behaviors. The results of the present study are in keeping with those obtained following central injection of NK3 agonists, and show that a behaviorally selective reduction of alcohol intake can be evoked also by peripheral administration of SENK.

Alcohol Drinking↗

Fate of cholesterol-rich liposomes after subcutaneous injection into rats.

The fate of small (30-60 nm) and large (about 400 nm diameter) liposomes composed of phosphatidylcholine or sphingomyelin and equimolar cholesterol and containing quenched carboxyfluorescein and 111In-labelled bleomycin after footpad injection of rats was investigated. Judging from the values of latent carboxyfluorescein in the plasma, phosphatidylcholine and sphingomyelin small liposomes entered the blood circulation intact, presumably via the lymphatics to reach 3 h after injection a peak of 16.9 and 23.1% of the dose per total blood, respectively. Of the 111In radioactivity given in phosphatidylcholine liposomes, about 32% was recovered in the liver. Hepatic uptake of 111In for sphingomyelin liposomes was lower (about 9%) reflecting their slower rate of clearance. No latent carboxyfluorescein could be detected in the blood after injection with phosphatidylcholine or sphingomyelin large liposomes and levels of 111In in the liver (and spleen) were very low. A proportionally much greater amount of liposomal 111In was intercepted by the popliteal and to a lesser extent, the lumbar lymph nodes. Such uptake was significantly higher (e.g. 463%) for small than for large (e.g. 195% per g popliteal nodes) liposomes. After foot pad injection of large liposomes into Walker 256 tumour-bearing rats, localization of 111In in the popliteal nodes was similar to that seen with control animals. However, 111In localization in the lumbar nodes was augmented more than 5-fold. These results suggest that large liposomes as used in this study, characterized by efficient drug entrapment, inability to reach the liver and spleen and improved localization in the lymph nodes of tumour-bearing animals may be preferable to vesicles of small size for the local treatment of lymphatic metastases.

Animals↗

Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain.

OBJECTIVE: To compare the efficacy and safety of SC depot medroxyprogesterone acetate (DMPA-SC 104) with that of leuprolide acetate in treatment of endometriosis. DESIGN: Phase 3, multicenter, randomized, evaluator-blinded, comparator-controlled trial. SETTING: Clinical trial sites in Canada and United States. PATIENT(S): Two hundred seventy-four women with surgically diagnosed endometriosis. INTERVENTION(S): Intramuscular injections of DMPA-SC (104 mg) or leuprolide acetate (11.25 mg), given every 3 months for 6 months, with 12 months of posttreatment follow-up. MAIN OUTCOME MEASURE(S): Reduction in five endometriosis symptoms or signs (dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, pelvic induration); change in bone mineral density (BMD), hypoestrogenic symptoms, bleeding, and weight. RESULT(S): The depot medroxyprogesterone acetate given SC was statistically equivalent to leuprolide in reducing four of five endometriosis symptoms or signs at the end of treatment (month 6) and in reducing all five symptoms after 12 months' follow-up (month 18). Patients in the DMPA-SC 104 group showed significantly less BMD loss than did leuprolide patients at month 6, with scores returning to baseline at 12 months' follow-up. No statistically significant differences in median weight changes were observed between groups. Compared with leuprolide, DMPA-SC 104 was associated with fewer hypoestrogenic symptoms but more irregular bleeding. CONCLUSION(S): Efficacy of DMPA-SC 104 was equivalent to that of leuprolide for reducing endometriosis-associated pain, with less impact on BMD and fewer hypoestrogenic side effects but more bleeding.

Adult↗

Effects of subcutaneous injections of a long acting moxidectin formulation in grazing beef cattle on parasite fecal egg reduction and animal weight gain.

Trials were conducted in Arkansas, Idaho, Illinois and Wisconsin using a common protocol to evaluate effectiveness and safety of a long acting (LA), oil-based injectable formulation of moxidectin in beef cattle grazing spring and/or summer pastures. At each site, 150 cattle (steers and/or heifers) were blocked based on pretreatment fecal strongyle egg counts (EPG) and then randomly assigned to treatments within blocks. Presence of naturally acquired parasitic infections, confirmed by presence of parasite eggs in feces, was a prerequisite for study enrollment. Within each block of three animals, two received moxidectin LA injectable on day 0 at a dosing rate of 1.0 mg moxidectin/kg b.w. into the dorsal aspect of the proximal third of the ear, and one received a placebo control treatment. Cattle were weighed before treatment and on day 55 or 56 (55/56) after treatment. Fecal samples were also collected from 10 randomly selected blocks of animals at each site on days 14, 28 and 55/56 for EPG quantification. Average daily gain (ADG) was computed over the posttreatment period. Data pertaining to ADG and EPG were combined across sites and analyzed by mixed model analysis of variance to assess the fixed effect of treatment and random effects of site, block within site and the treatment by site interaction. Compared to placebo-treated controls, the geometric means of fecal EPG counts from cattle treated with moxidectin LA injectable were reduced 99.8% 14 days after treatment, 99.1% 28 days after treatment and 96.7% 55/56 days after treatment. Rate of weight gain by cattle treated with moxidectin LA injectable was 0.59 kg/day, or 23% (0.11 kg/day) more than placebo-treated controls (P<0.05). None of the cattle treated with moxidectin LA injectable exhibited signs of macrocyclic lactone toxicosis. Summarized across all study sites, proportions of cattle that received concurrent therapeutic treatments were similar among treatment groups. Study results demonstrate that moxidectin cattle LA injectable administered at a dosing rate of 1.0 mg moxidectin/kg b.w. to grazing beef cattle was effective and safe.

Analysis of Variance↗

Lymphatic uptake and biodistribution of liposomes after subcutaneous injection. II. Influence of liposomal size, lipid compostion and lipid dose.

The present paper reports on the results of a systematic study on liposome variables potentially affecting lymphatic disposition and biodistribution of liposomes after sc injection. Liposomal size was found to be the most important factor influencing lymphatic uptake and lymph node localization of sc administered liposomes. Lymphatic uptake from the s.c. injection site of small liposomes (about 0.04 microm) was relatively high (76% of the injected dose (%ID)) as compared to large, non-sized liposomes, which remained almost completely at the site of injection. Small liposomes were less efficiently retained by regional lymph nodes than larger liposomes. Liposomal lipid composition did not influence lymphatic uptake with one exception: Lymphatic uptake was decreased in case of neutral liposomes composed of (DPPC). Lymph node localization was substantially enhanced by inclusion of phosphatidylserine (PS) into the liposomal bilayers. Saturation of lymphatic uptake and lymph node localization did not occur over a large liposomal lipid dose range, illustrating the efficient performance of lymph nodes in capturing s.c. administered particles.

Animals↗

The performance of subcutaneously injected Fertinex when used as the sole gonadotropin for in vitro fertilization stimulation.

OBJECTIVE: To assess the performance of Fertinex (urofollitropin; Serono Laboratories, Norwell, MA) in stimulating the development of multiple follicles and initiating subsequent pregnancy in patients undergoing controlled ovarian hyperstimulation (COH) for IVF. DESIGN: Prospective observational study. SETTING: Private assisted reproductive technology (ART) center. PATIENT(S): Ninety-three women who underwent an IVF cycle of COH in which Fertinex was used as the sole gonadotropin. INTERVENTION(S): The COH protocol included Fertinex with leuprolide acetate down-regulation in the late luteal phase or the early follicular phase. Embryo transfer was performed after 3 days of culture. MAIN OUTCOME MEASURE(S): Stimulation parameters, embryologic data, and pregnancy rates (PRs). RESULT(S): Ninety-three patients underwent 97 cycles of COH, with a cancellation rate of 13.4%. The clinical PR was 42% per initiation, 49% per retrieval, and 51% per transfer. Shorter stimulation periods, lower estradiol levels either per follicle punctured or per oocyte retrieved, and slower embryo development were observed. Patients responded to Fertinex in three distinct stimulation patterns: escalating response with a peak estradiol level of < or =3,000 pg/mL, escalating response with a peak estradiol level of >3,000 pg/mL, or escalating response characterized by a drop in the estradiol level or a plateau before hCG administration. All three responses had similar PRs. CONCLUSION(S): Fertinex can be used successfully as the sole gonadotropin for COH in ART without compromising high PRs. Traditional estradiol response curves or cancellation criteria may not apply when Fertinex is used as the sole gonadotropin for COH in ART.

Adult↗

c-Fos expression in rat spinal cord induced by scorpion BmK venom via plantar subcutaneous injection.

The aim of this study was to assess the cell-type and distribution of highly activated neurons in rat spinal cord underlying nociceptive responses induced by scorpion BmK venom using Fos immunohistochemistry. BmK venom was intraplantarly injected into one hind paw of a conscious rat. Fos-like immunoreactive neurons were found to predominantly distribute at L4-5 segments in the rat spinal cord after BmK venom application. c-Fos labeling was most dense in the medial half portion of laminae I-II, moderately dense in laminae V-VI and less dense in laminae III-IV, VII-X. c-Fos labeling could be detected at 0.5 h, reached the peak at 2 h, decreased steeply from 4 h and then almost disappeared at 24 h. Ten to fifty micrograms of BmK venom was deemed to be a sufficient dosage to evoke c-Fos expression. On the other hand, c-Fos expression induced by BmK venom could be suppressed partially by systemic morphine in a dose-dependent manner. The results suggest that the different extent of activities of neuronal subpopulation in the spinal cord involved in nociceptive transmission manifesting as c-Fos expression, were mainly correlated with mechanisms underlying the generation, maintenance and/or modulation of spontaneous pain and hyperalgesia evoked by BmK venom.

Afferent Pathways↗

Selective destruction of medial septal cholinergic neurons attenuates pyramidal cell suppression, but not excitation in dorsal hippocampus field CA1 induced by subcutaneous injection of formalin.

Using extracellular recording techniques in urethane- (1g/kg, i.p.) anaesthetized rats, we investigated the influence exercised by medial septal cholinergic neurons on dorsal hippocampus field CA1 neural responses to a hind paw injection of formalin (5%, 0.05 ml, s.c.). Cholinergic neurons of the medial septal region were destroyed by local microinjection of the immunotoxin 192 IgG-saporin. Compared to control vehicle microinjected animals, immunotoxin-treatment attenuated the amplitude, but not frequency, of CA1 theta induced by intraseptal injection of carbachol. This suggested a selective destruction of medial septal cholinergic neurons by the immunotoxin. Such destruction also abolished; (i) intraseptal carbachol-induced suppression of CA1 population spike, and (ii) stimulation-intensity dependent increase in amplitude, but not frequency, of theta evoked on electrical stimulation in the region of oral part of pontine reticular nucleus. Further, in comparison to vehicle-treated animals, selective cholinergic destruction attenuated formalin-induced; (i) theta activation, (ii) suppression of CA1 pyramidal cell population spike and dendritic field excitatory post-synaptic potential, (iii) inhibition of complex spike cell extracellular activity, and (iv) excitation and theta-rhythmicity of local putative GABAergic interneurons. However, pretreatment with the immunotoxin did not alter the strength and proportion of complex spike cells excited following injection of formalin. From these findings we suggest that medial septal cholinergic neurons mediate, at least partly, the amplitude of theta and pyramidal cell suppression via an inhibitory network involving CA1 interneurons. The data also indicates that during formalin theta, the cholinergic-mediated inhibitory processing does not modulate the strength and selectivity of complex spike cell excitation. This points to formalin-induced, non-overlapping inhibitory and excitatory processes that might have different functional relevance.

Animals↗