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Improvement of growth and food utilization by human recombinant growth hormone in uremia. We compared growth rate, food conversion ratio and morphology of the growth zone in female Sprague-Dawley rats with subtotal nephrectomy or sham operation. Both groups were either given vehicle or 1.4 IU/day recombinant human growth hormone (GH) by s.c. osmotic minipump, or 2.5IU twice daily intraperitoneally for 14 or 20 days, respectively. Compared to uremic rats infused with vehicle, infusion of GH significantly (P < 0.01) improved growth; that is, it increased gain of weight (Δ27.0 ± 7.7g vs. 11.6 ± 4.9g) and length (Δ1.8 ± 0.3cm vs. 1.12 ± 0.44cm) in ad libitum fed uremic rats. This was accompanied by increased food utilization ratio (0.146 vs. 0.065g weight gain per g food intake). A similar increment of growth and food utilization ratio was also observed in GH versus solvent infused controls, either pairfed as for the uremic animals or fed ad libitum. Despite administration of GH, growth was not completely restored to normal in uremic animals. Circulating immunoreactive IGF I was not significantly increased by GH infusion in either uremic animals or controls. Histological analyses of the proximal tibia showed increased rate of longitudinal growth, as evaluated by tetracyclin-labeling, and increased volumetric density of primary spongiosa with unchanged width of primary spongiosa trabecules when GH was infused in uremic animals. The data suggest that growth impairment in the uremic rat is partially responsive to GH, and this is not accompanied by an increase of circulating IGF I. Therapeutic trials with recombinant GH in uremic children appear justified.

Cholecystokinin octapeptide (CCK-8) is known to suppress feeding in sheep, pigs, golden hamsters and rats following acute intracerebriventricular (i.c.v.) injection. In this study, we report the effects of chronically administered i.c.v. CCK-8 on long-term food intake in rats. After baseline food intake was established over a period of 3 days, rats were implanted with Alzet osmotic minipumps, which delivered 1.0 μl/h. Three groups of animals were prepared which received saline (vehicle) or CCK-8 at 12.25 μg/day (low dose) or CCK-8 at 122.5 μg/day (high dose). Surgical preparation of the animals with the intraventricular cannula and the osmotic minipump resulted in an initial reduction in food consumption in all groups. In the saline group daily food consumption returned to presurgery values by day 4. Similar results were observed with the low dose of CCK-8. In contrast, in animals receiving the high concentrations of CCK-8, the initial fall in feeding was more prominent and though it rose during the 7-day infusion interval, it remained statistically below control during this period. After termination of the infusion, daily food consumption rose to normal levels during the next 3 days. For comparison, the cumulative difference between daily food consumption over the period of 8 days during infusion and pre-infusion control was 39.9 ± 10.0 g/24 h in the saline group. In CCK-8-infused animals, food consumption after pump implantation was reduced by an integrated value of 35.5 ± 5.0 g/24 h at low dose and 117.4 ± 20.2 g/24 h at high dose. Thus, by all indices, i.c.v. infusion of CCK-8 at high dose, but not at low dose resulted in a significant reduction of food intake as compared ti saline (P < 0.05). Water intake was not not altered by the infusion of CCK-8 at low or high dose vs saline.

The effect of continuous intracerebroventricular (i.c.v.) administration of naloxone on the duration of individual bouts of hibernation was investigated in the golden-mantled ground squirrel (Citellus lateralis). Following entrance into hibernation, naloxone was continuously administered by an osmotic minipump at a rate of 1 microliter/h through a chronically implanted unilateral i.c.v. cannula guide. Naloxone (1, 5 and 7.5 micrograms/microliter) produced a dose-dependent reduction in hibernation bout duration ranging from 1 to 4 days (13.9-62.3% of expected bout duration). These data suggest that selected endogenous opioid system neurons may contribute to the CNS maintenance of the hibernating state and, consequently, to the overall conservation of energy in this species.

We determined the concentration and chemical status of arsenic in the placentas of hamsters following continuous exposure via the osmotic minipump to minimally and frankly teratogenic doses of arsenate. Close to 70% of the placental arsenic is bound to macromolecules, two-thirds of which is dialyzable. The remaining 30% of arsenic consists of low molecular weight species, predominantly inorganic arsenic. This mix is the same for minimally teratogenic and frankly teratogenic doses of arsenate.

Ventricular myosin ATPase activity, V1 isomyosin content and serum T3 (tri-iodothyronine) values decrease with age in male Fischer 344 rats. To determine if the age decrement in ATPase activity and V1 isomyosin content are caused by decreased T3 levels or an age-related decrease in V1 isomyosin induction by T3, 3-, 12- and 24-month-old male Fischer 344 rats were given constant T3 infusions by osmotic minipump. Rats at all ages were given 0.75, 5 and 15 micrograms(/100 g per 24 h) doses of T3, whereas 12- and 24-month-old rats were given an additional 0.4 microgram dose. In control rats, T3 levels decreased from 97 +/- 2.7 at 3 months to 75 +/- 4.7 ng/100 ml at 24 months. Likewise, Ca2+-activated myosin ATPase activity decreased from 1.04 +/- 0.05 to 0.68 +/- 0.05 mumol of Pi/min per mg of protein, and the relative proportion of V1 of isomyosin decreased from 90 +/- 4.0 to 26 +/- 2.0%. The lowest (0.4 microgram) T3 dose, which was sufficient to restore T3 levels in 24-month-old animals to 3-month control values, abolished the age decrement in myosin ATPase activity and markedly increased the proportion of V1 isomyosin present in the ventricle. These findings indicate that the senescent ventricle responds readily to small doses of T3 and strongly suggest that the age decrement in serum T3 levels is sufficient to contribute to the age-related decrease in myosin ATPase activity and V1 isomyosin content. Since these parameters correlate with ventricular contractility, the age decrement in T3 levels may also contribute to the decreased ventricular contractility and cardiac output observed in senescent rats.

Summary. Implants of progesterone on the day of dioestrus II in the hamster induced on the following day an increase in circulating levels of progesterone (6\m=.\0\m=+-\0\m=.\7ng/ml, N = 8; sesame oil controls

We have studied some temporal aspects of the feedback inhibition of TSH secretion in unanesthetized rats using two patterns of T3 administration. Rats were thyroidectomized and prepared with chronic jugular catheters through which sequential blood samples were obtained and TRH was administered. Physiological amounts of T3 replacement (280–566 ng/100 g-day) were delivered to the rats by one of two methods: 1) continuous sc infusion by use of the Alzet osmotic minipump or 2) twice daily (800 and 2000 h) sc injections. In rats receiving 280 or 350 ng T3/100 g-day by constant infusion, plasma T3 concentrations were maintained at near-normal levels (50–60 ng T3/dl), but plasma TSH levels rose progressively. The plasma TSH concentration was significantly (P < 0.05) elevated above prethyroidectomy levels as early as 48 h post thyroidectomy and continued to rise throughout 144 h. Constant infusion of 566 ng T3/100 g-day resulted in plasma T3 levels above normal and the maintenance of normal plasma TSH. Rats recei...

The use of tritiated thymidine labelling given by continuous delivery over long periods by means of an implanted osmotic minipump is a convenient method of accurately determining the rate of cellular proliferation in various tissues, but is especially advantageous for the periodontal ligament (PDL), the fibroblasts of which turn over at an extremely low rate. This technique was used to examine the hypothesis that differences exist between cell turnover in normal hamsters (N.D.) and those which had been placed on a periodontal disease inducing diet (S.S.D.). Turnover rates were then calculated for PDL and epithelial attachment (EA) for N.D and S.S.D animals before and after disease had been induced. No effect of disease was noted for either PDT or EA. However, the technique was sufficiently sensitive to demonstrate a significant effect of age on the turnover of cells in the epithelial attachment.

We have studied the cytotoxicity of bleomycin (4--10 u/kg/day for 6 days) given by continuous i.p. infusion (using an osmotic minipump) compared to daily i.p. bolus administration, against P388 leukaemic spleen colony-forming-units(LCFU-S). Continuous i.p. bleomycin at 8 u/kg/day caused a 0.5 log greater reduction of LCFU-S than did an identical dose given by intermittent bolus administration. The infusion minipump provided constant bleomycin plasma levels of 0.62 +/- 0.03 mu/ml and a total plasma AUC (area under the plasma decay curve) of 89.0 mu.h/ml for 6 days at 8 u/kg/day. Intermittent bolus bleomycin at 8 u.kg/day had a terminal-phase plasma t1/2 of 15 min and a total 6-day plasma AUC of 90.8mu.h/ml. These pharmacokinetic data validate the osmotic minipump as a constant drug-delivery system, and suggest that the two administration schedules resulted in equal total bleomycin dosages. Although high peak bleomycin plasma levels (i.e. 32 mu/ml) were achieved with the intermittent bolus administration, continuous-infusion bleomycin's greater inhibition of LCFU-S was probably related to the drug's schedule-dependent cell-killing characteristics. The results of this study provide further rationale for the continuing use of infusion bleomycin schedules in cancer patients.

Delta sleep-inducing peptide has been shown to exert extra-sleep effects as well as effects on sleep. In this study, the concentrations of DSIP-like immunoreactivity were measured by radioimmunoassay in the plasma of spontaneously hypertensive rats (SHR). They were found to be about 25% higher in SHR plasma than in the plasma of the normotensive Wistar-Kyoto (WK) controls. DSIP was then infused for 10 days by osmotic minipump (200 micrograms/kg/day) into SHR. This resulted in in maintenance of BP at a level of about 200 mm Hg as compared with the significant increase to about 220 mm Hg after 10 days in the SHR controls infused with 0.9% NaCl. After daily SC injection of a single dose of 200 micrograms/kg DSIP for each of 5 days in SHR, findings were similar. The results raise the possibility of an involvement of DSIP in the regulation of BP in SHR.

The objective of this study was to determine whether anti-oestrogens (nafoxidine, MER-25) would block the suppressive effects of ACTH on gonadotrophin secretion in immature rats. Female rats were castrated at 25–26 days of age, and an Alzet osmotic minipump containing ACTH (1–24) or saline was implanted in each animal. ACTH was administered at a rate of 1 IU/day by constant infusion. Beginning on the day of surgery, animals were injected daily for 5 days with 0.25, 5 or 25 μg/100 g body weight of nafoxidine or 5 mg MER-25 and sacrificed on the sixth day following castration. ACTH lowered serum LH concentrations and increased pituitary LH levels. Serum androstenedione concentrations were more than two times greater in ACTH-infused than in control rats, but serum oestrone levels were not affected. Serum testosterone and oestradiol concentrations in ACTH-infused rats remained below levels of detection. Administration of 0.25 μg of nafoxidine prevented the suppressive effects of ACTH on serum LH. Serum levels of LH in these animals were comparable to saline-treated controls (418 ± 94 vs 443 ± 73 ng/ml). The two higher doses of nafoxidine and MER-25 were ineffective in suppressing the actions of ACTH on serum LH. MER-25 reduced serum LH values in both controls and ACTH-infused rats. Serum FSH concentrations were not altered by ACTH or nafoxidine treatment. MER-25 elevated pituitary FSH concentrations in both control and ACTH-infused rats. These data suggest that the inhibitory effect of ACTH on LH secretion in immature rats is mediated by an oestrogenic steroid, since this action can be blocked by simultaneous treatment with a low dose of the anti-oestrogen, nafoxidine.

A number of investigators have recently used osmotic minipumps to continuously deliver the neurotoxin 6-hydroxydopamine (6-OHDA) to kitten cerebral cortex for periods up to 7 days. Because this compound is known to be particularly labile, we studied the stability of 6-OHDA stored under conditions similar to those found in an osmotic minipump. In 0.4% ascorbic acid, 4 mM 6-OHDA-HBr was found to be stable for at least one week as determined by (1) assay of the drug by high performance liquid chromatography and electrochemical detection and (2) test of the drug's ability to deplete mouse heart norepinephrine.

To assess the pathophysiological role of atrial natriuretic factors in the regulation of blood pressure, we studied the effect of chronic infusion of a synthetic atrial natriuretic factor of 25 amino-acid residues on blood pressure and sodium-water excretion. Experimental subjects were rats with hypertension made by chronic infusion of vasopressin on regular intakes of sodium or on sodium loading with 1% NaCl as drinking water. When a subdepressor dose (150 micrograms/kg/day) of synthetic atrial natriuretic factor was delivered via an osmotic minipump into the jugular vein simultaneously with 7.2 U/kg/day of vasopressin infused intraperitoneally by another osmotic minipump, the expected elevation of systolic blood pressure was completely inhibited. This was not accompanied by any changes in urine volume and urinary sodium excretion. The antihypertensive effect was sustained throughout the experimental period lasting 3 days in rats on regular sodium intake (p less than 0.01) or on sodium loading with 1% NaCl as drinking water (p less than 0.01). These results indicate that a subdepressor dose of synthetic atrial natriuretic factor can modulate the vasopressor effect of vasopressin. Therefore it is suggested that an atrial natriuretic factor may be involved in the regulation of blood pressure via its antagonizing effect to vasopressin.

The construction of a multiple-cannula headpiece, its implantation into the rat brain, and its use in intracranial injections is described. The headpiece is rapidly and cheaply produced from common hospital and laboratory supplies once several machined metal parts have been made, and its construction is easily adapted to changes in injection technique, e.g., infusion by osmotic minipump.

when using laboratory animals (e.g., mice) for phencyclidine (PCP) tolerance studies, an essential part of the procedure is to administer the PCP in such a way that the animals received adequate doses of the drug at frequent enough intervals to reach and main train the desired levels of tolerance or employ a osmotic minipump which is either suitable or convenient to develop a high degree of tolerance to PCP in a large number of animals in a short period. However, these methods are unfit for routine work because of repeated daily injections consume too much time and osmotic minipump comes expensive. Therefore, in this paper we attemped to develop PCP pellet suitable for tolerance development The s.c. implantation of a 10 or 20 mg PCP pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to PCP than that produced in mice receiving daily i.p. injection of, 10 or 20 mg/kg, PCP-HCL. Assessment of and degree of tolerance to PCP by PCP peller implantation and daily injection of PCP-HCL were evidenced by a degree of decrease in the duration of motor incoordination after the challenge with, 20 mg/kg, PCP-HCL 24 h after removal of PCP pellets or a last injection of PCP-HCL. These studies may demonstrate a substantial methodological improvement in producing a high degree of tolerance to PCP in a short period of time by means of the s.c. pellet implantation technique.

Continuous intraperitoneal infusion of a macrophage colony-stimulating factor (M-CSF or CSF-1) for 6 d resulted in a 2.3-fold increase in the frequency of progenitor cells (CFUc) of macrophages in femoral marrow in C3H/HeN mice but there was no significant increase in the number of blood leukocytes in these animals. Infusion of bacterial lipopolysaccharide (LPS) also increased femoral macrophage CFUc frequency to the same extent as the above. Furthermore, the effect of the M-CSF preparation was much less pronounced in LPS-resistant C3H/HeJ mice than in LPS-sensitive C3H/HeN mice. The results show that the effect of M-CSF on bone marrow CFUc is marginal, even when it is administered in large amounts in the animals.

This paper describes a simple-to-build minipump-chemitrode assembly which can be used for long term electrophysiological, chemical and behavioural studies. This system consists of an osmotic minipump, a cannula and an array of nine electrodes which are connected to a miniature Winchester Socket. A detailed plan for construction of both the chemitrode and the minipump-chemitrode is given together with some suggestions for possible usages in brain research (such as kindling). The osmotic minipump consists of a collapsible reservoir of flexible, impermeable material, surrounded by a sealed layer containing an osmotic agent—all of which is contained by a semipermeable membrane. Imbibed water generates hydrostatic pressure on the flexible lining of the reservoir, gradually compressing it, producing a constant flow of its contents through the delivery portal.

A recurrent malignant glioma was treated with cisplatin delivered directly into the tumor. The drug was delivered via 68 small catheters distributed evenly throughout the tumor area. Each catheter was connected to an osmotic minipump that delivered 0.5 ml of drug solution each hour for 10 days. There were no side effects from the catheter implantation, chemotherapy, or catheter removal. Although the chemotherapy halted progression of the tumor, it recurred, and the patient died 6 months after treatment.

A rabbit model of endophthalmitis was used to test the efficacy of an osmotic minipump delivery system as compared to standard intravitreal injection of the antibiotic, Staphylococcus aureus was inoculated into the vitreous cavity, and elimination of microorganisms was compared with use of intravitreal administration of 100 micrograms of gentamicin sulfate by either single pars plana injection or the continuous four-day administration of drugs to the vitreous via pars plana tubing connected to the minipump implanted subcutaneously near the rabbit's ear.

One hour before a contusive spinal cord injury either compound MK-801 or compound U-50488H was injected intraperitoneally, and a 14-day-delivery osmotic minipump containing the same drug was placed subcutaneously at the time of surgery. The motor and sensory behavior of the animals was measured over the following 30 days. Both MK-801 and U-50488H treatments had a statistically significant neuroprotective effect. The number of neurons per unit area outside the lesion epicenter was significantly (P less than 0.01) greater in the drug-treated animals (MK-801, 298.9 +/- 74.8 neurons/mm2; U-50488H, 242.7 +/- 16.5 neurons/mm2) than in untreated controls (73.3 +/- 9.3 neurons/mm2). Recovery of sensory and motor behavior was limited but significant differences were observed when drug-treated rats were compared with untreated controls. The effects of the two drugs were not additive for any of the variables studied.

Rats with unilaterally sectioned sciatic nerves were continuously administered naloxone HCl (80 or 800 micrograms/h) or equivalent volumes of saline (1 or 10 microliters/h) subcutaneously via osmotic minipumps over a 2 or 5 week period. Rats receiving 80 micrograms/h naloxone for 5 weeks exhibited significantly less self-mutilation (autotomy) of the denervated foot than saline controls or rats receiving 80 micrograms/h naloxone for 2 weeks. The nociceptive threshold of intact rats infused with the same dose of naloxone was tested on a hot plate. In these animals there was no influence on the nociceptive threshold during naloxone administration for 1 week. Autotomy was also reduced in rats infused with 800 micrograms/h naloxone. The nociceptive threshold of intact rats infused with this dose of naloxone or an equivalent volume of saline (10 microliters/h) was increased, suggesting that the presence of the larger osmotic pump caused analgesia.

This study investigated the differential effects of chronically administered nicotine and saline on motor activity in the rat. Nicotine was administered via a subcutaneously implanted osmotic minipump to effect an 8 hour off, 16 hour on, flow. Subjects were 48 male and 48 female albino rats, each about 165 days old. Activity was monitored every hour for 192 consecutive hours. Results indicated that the female animals were more active than the males,and that animals receiving nicotine were significantly more active on the first two days of drug administration than control animals; however, by the fourth day there were no significant differences between the activity levels of animals that received nicotine and those of control animals.

Development of tolerance to phencyclidine (PCP) was assessed in male ICR mice, using motor incoordination as a parameter. The implantation of a PCP (1–3 mg/ day/mouse for 1–5 days)-containing osmotic minipump, induced tolerance, as evidenced by a gradual reduction of the duration of motor incoordination. The degree of tolerance exhibited dose and time dependency. Even after the removal of the PCP pump (1 mg/day/mouse for 5 days), the tolerance remained to the same degree for at least 4 days. The hepatic microsomal cytochrome P-450, cytochrome b 5 and nicotinamide adenine dinucleotide phosphatase (NADPH)-cyctochrome c reductase activities were found to be elevated in tolerant mice (2 mg/ day/mouse for 5 days). The half-life of PCP in the brains of tolerant mice was likewise decreased. These data indicate a dispositional tolerance for PCP. It appears that the administration of PCP by the osmotic minipump offers a convenient method for inducing PCP tolerance.

The effects of melatonin on blood pressure and heart rate were studied in 23-week-old male spontaneously hypertensive rats. Melatonin infused i.p. at a dose of 6 mg/rat per day for 5 days using an osmotic minipump produced a significant reduction of blood pressure and a slight but significant decrease of heart rate in the conscious and unrestrained state. These cardiovascular effects of melatonin developed gradually. Plasma renin concentration tended to decrease after melatonin treatment. These results demonstrate that melatonin has an antihypertensive action. The mechanism of the antihypertensive action of melatonin requires further study.

Methods: The sample was divided in 20 rats from the control group (CG); 20 rats submitted to an experimental model of ibrosis, in which the rats were uninefrectomized, drank water with 1% NaCl during the protocol and received aldosterone through an osmotic minipump (AG); and 20 rats submitted to the same experimental model were treated with digitoxin in a daily dose of 100 μg/Kg (DAG). All animals were submitted to high resolution echocardiography at the beginning and the end of the study. Serum B-type natriuretic peptide (BNP) levels were measured by Elisa. After 6 weeks of treatment the animals were euthanized, Picrosirius Red stain was used to quantify myocardial collagen, and gelatin zymography was performed for metalloproteinases-2 and metalloproteinases-9 activity of the heart samples.