Delivery In Rats Research Articles

Impaired passive avoidance acquisition in Sprague–Dawley and Lewis rats after restraint and cold stress

The study examined the effects of restraint combined with cold water stress (IMO+C) on learning and memory of Sprague–Dawley (S–D) and Lewis (LE) rats in the passive avoidance task. The procedure started with 6 days of adaptation to the apparatus during which the recorded latencies to enter the dark compartment were used to assess the process of habituation. On the training day rats were exposed to IMO+C for 60 min and the stressor exposure terminated 1 h before the acquisition trial. Retention trials started 24 h later. To evaluate the possible long-term consequences of the acute and repeated stress presentation on the performance of the two strains with diverse activity of hypothalamic–pituitary–adrenal axis, this procedure was performed three times including stress application (Parts 1–3). Finally, an identical procedure was performed without stress (Part 4). An immediate behavioural effect of the stressor exposure was observed in an increase of latencies to enter the dark compartment before the shock delivery in rats of both strains; this enhancement approached significance after the second and third exposure to the stressor (Parts 2 and 3). Control animals of both strains acquired passive avoidance response after training in Parts 2–4. IMO+C produced significant impairment of this response irrespective of the strain. The three-time repeated exposure did not influence the ability to learn the task in the final procedure without stress. Differences in behaviour of S–D and LE rats were observed already during the first adaptation period. LE rats exhibited longer latencies upon the first exposure to the novel environment compared to S–D rats. Also only LE rats displayed habituation. In Part 4 marked strain differences in the latencies both before and after training were recorded. The results show that the repeated exposure to the IMO+C stressor proved to be a strong amnestic stimulus but without persisting consequences for the ability of rats to acquire the learning task.

Interferon-α2b Secretion by Adenovirus-Mediated Gene Delivery in Rat, Rabbit, and Chimpanzee Results in Similar Pharmacokinetic Profiles

Gene delivery, with subsequent protein synthesis and secretion, in vivo has been proposed as an alternative way to deliver a therapeutic protein to the systemic circulation. Interferon-α (IFN) protein is effective in the treatment of viral and malignant diseases but has short serum half-life that requires frequent administration. An E1 region-deleted adenovirus vector encoding human IFN-α2b gene driven by the cytomegalovirus immediate early promoter (rAd-IFN) was generated to assess the serum concentration–time profiles of expressed IFN protein in animal models. Intravenous administration of rAd-IFN, normalized for body weight, resulted in dose-dependent serum IFN concentrations that persisted 8–40 days with similar concentration–time profiles in rats and rabbits. We sought to determine if serum concentration–time profiles in the rat and rabbit animal models would be predictive for a larger animal and would therefore be relevant models for potential dosing of human patients. Two chimpanzees (∼70 kg) dosed with rAd-IFN by intravenous administration normalized to body weight achieved serum IFN concentration–time profiles similar to those observed in rats and rabbits. The role of the immune response in limiting the persistence of transgene expression was highlighted by the persistence of serum IFN concentrations for over 200 days in beige/SCID immunodeficient mice. These studies suggest that serum concentration of secreted transgene products after gene delivery in small animal models may be highly predictive for larger species and will help define dosing strategies in human patients.

Serial cerebrospinal fluid sampling in a rat model to study drug uptake from the nasal cavity

Drug transport from the nasal cavity to the brain has gained much interest in the last decade. In the present study, a model was developed to determine the uptake of drugs into the cerebrospinal fluid (CSF) after nasal delivery in rats. CSF samples were taken using a cisternal puncture method. In this method, a needle is advanced through the skin and muscles overlying the atlanto-occipital membrane into the cisterna magna, while the rat is fixed in a stereotaxic frame. This method appears to be superior over cannulation of the atlanto-occipital membrane for CSF sampling. The major advantages of the puncture method is the ability of serial and simultaneous CSF and blood sampling for over 2 h in the same rat. To obtain maximal drug absorption from the nasal cavity and uptake into CSF, different positions of the rat's head (upright-90°, supine-90°, supine-45° and supine-70° angles) were tested in nasal delivery studies using hydrocortisone (HC) as a model drug. Putting the rat in the supine-90° angle position increased the absorption of HC into plasma and CSF 2-fold compared to the upright-90° angle position. The supine-70° angle position did not change the HC plasma and CSF levels compared to the supine-90° angle position. However, the supine-70° angle position showed the fastest CSF sampling rate, enabling more accurate CSF sampling and therefore preferred for further studies. In conclusion, the cisternal puncture method using the supine-70° and 90° angle position is a suitable method to study drug transport from the nasal cavity into the CSF, with the ability of multiple CSF sampling.

Skin-targeted gene transfer using in vivo electroporation.

The skin is an important target for gene transfer because of its easy accessibility. Using plasmid DNA expressing rat erythropoietin (pCAGGS-Epo) as the vector, we previously demonstrated long-term Epo delivery in rats by muscle-targeted gene transfer using in vivo electroporation. Here we examined whether this electroporation approach could be applied to gene delivery in rat skin. To optimize gene transfer, we tested the efficiency of skin-targeted Epo gene transfer with three types of electrodes at three different electrode voltages. Each rat was injected intradermally with a total of 800 microg of pCAGGS-Epo, in the abdominal area. Plate-and-fork-type electrodes were effective for Epo delivery by skin-targeted gene transfer at low voltages (12 approximately 24 V). The vector-derived Epo mRNA was expressed only at the DNA injection site. The Epo gene was expressed in a dose-dependent manner, the expression persisted for 7 weeks, and hematocrit levels were increased for 11 weeks. Skin injection with pCAGGS-lacZ showed lacZ gene expression in the epidermis on day 1 after injection and in the subcutaneous muscle layer on day 7. Slight skin damage due to the gene transfer procedure was evident on day 1, but absent by day 7. These results demonstrate that skin-targeted pCAGGS-Epo transfer by in vivo electroporation at low voltage is a useful procedure for the short-term delivery of Epo.

The effects of cervical application of inhibitors of inducible nitric oxide synthase, cyclooxygenase-1, and cyclooxygenase-2 on delivery in rats

Objective: To investigate the effect of cervical application of nonselective and selective inhibitors of nitric oxide synthases—N -nitro-L -arginine methyl ester, L -N -iminoethyl-lysine, and aminoguanidine—as well as inhibitors of cyclooxygenases—indomethacin, and nimesulide—on timing of delivery and fetal death and disease in pregnant rats. Study Design: In a series of experimental protocols, timed-pregnant Sprague-Dawley rats (length of pregnancy, 22 days) were randomly allocated to daily cervical applications of (1) 0.04 mg (n = 6), 0.4 mg (n = 6), 4 mg (n = 6), or 40 mg (n = 6) L -N -iminoethyl-lysine or vehicle (n = 12) on days 19 to 22 of pregnancy; (2) 50 mg aminoguanidine (n = 6), 150 mg aminoguanidine (n = 6), or vehicle (n = 10) on days 19 to 22 of pregnancy; (3) 3 mg indomethacin (n = 6) or vehicle (n = 6) on days 19 to 22 of pregnancy; (4) 12.5 mg/kg nimesulide (n = 8), 25 mg/kg nimesulide (n = 8), 50 mg/kg nimesulide (n = 12), or vehicle (n = 12) on days 19 to 22 of pregnancy and 50 mg/kg nimesulide (n = 23) or vehicle (n = 23) on days 14 to 22 of pregnancy; (5) 50 mg/kg nimesulide (n = 10), 50 mg aminoguanidine plus 50 mg/kg nimesulide (n = 10), 50 mg aminoguanidine (n = 10), or vehicle (n = 10) on days 14 to 22 of pregnancy. The following variables were evaluated: proportion of animals that were delivered on day 23, time to delivery of the first pup (midnight on day 22 was considered to be 0 hour), number of stillborn pups, and average pup weight of each litter. Results: Unlike L -N -iminoethyl-lysine, aminoguanidine, and indomethacin, 50 mg/kg nimesulide applied on the cervix daily for 8 days significantly increased the proportion of animals that were delivered on day 23 (18 of 23 versus 7 of 23; P =.003) and the time to delivery of the first pup by a mean of 10.8 hours (P <.001). Shorter treatment with nimesulide for 4 days increased only the time to delivery of the first pup at the 25-mg/kg dosage (P =.008). Simultaneous application of aminoguanidine and nimesulide significantly (P =.008) prolonged pregnancy to a degree similar to nimesulide alone. The experiment with N -nitro-L -arginine methyl ester was aborted because of severe maternal side effects. Unlike pups in the L -N -iminoethyl-lysine, aminoguanidine, and nimesulide groups, significantly more pups in the indomethacin group died in utero compared with the control group (36.1% versus 3.1%; P <.001), and the surviving pups had lower birth weights (P <.001). Conclusions: In an animal model, nimesulide was effective in delaying the onset of labor, was well tolerated during pregnancy, and affected cervical ripening directly independent of progesterone withdrawal. Conversely, cervical application of nitric oxide synthase and nonselective cyclooxygenase inhibitors do not extend the duration of pregnancy in the dosages studied, and some are associated with significant adverse effects in the mothers and fetuses. (Am J Obstet Gynecol 2001;185: 959-65.)

Interleukin-10 Administration and Bacterial Endotoxin-Induced Preterm Birth in a Rat Model

In Brief OBJECTIVE To determine whether intrauterine infusion of interleukin-10 prevents preterm delivery in rats treated with endotoxin. METHODS Pregnant rats underwent implantation of uterine catheters and were randomly assigned to receive intrauterine infusion of either normal saline, 50 μg lipopolysaccharide endotoxin, or 50 μg lipopolysaccharide with 500 ng interleukin-10 administered either concurrently or 24 hours later. The interval from infusion to delivery for each group was recorded, along with the number of live born pups and their birth weight. We calculated that to obtain a power of 80%, assuming a 24-hour difference in the treatment to delivery times between the test and control subjects, at least six animals would be needed in each group. RESULTS In females receiving lipopolysaccharide (50 μg) alone, the interval to delivery (P < .05), live birth rate (P < .05), and pup weight (P < .001) were reduced compared with the saline-infused controls. In contrast, females receiving interleukin-10 at the time of the endotoxin challenge or 24 hours after delivered at term with no difference in litter size or live birth weight compared with the controls. CONCLUSION Animals treated with both lipopolysaccharide and interleukin-10, administered concurrently or 24 hours after the endotoxin challenge, delivered normal weight pups at term with a similar litter size as the saline-infused controls. Interleukin-10 appears to be effective in preventing endotoxin-induced preterm birth and fetal wastage in pregnant rats. Interleukin-10 prevents endotoxin-induced preterm birth in a rat model.

Growth hormone treatment after cesarean delivery in rats increases the strength of the uterine scar

Objective: We sought to determine whether postcesarean treatment of rats with growth hormone (GH) affected the strength of the uterine incision in the puerperium and in a subsequent pregnancy. Study Design: Forty-eight near-term pregnant rats were delivered by cesarean section. Half received subcutaneous recombinant human GH (2.0 mg·kg–1·d–1) for 7 days; control animals received saline injections. Four weeks after delivery, the uterine bursting pressure was determined in 5 treated and 5 control animals. Eight rats in each group were used to study uterine hydroxyproline concentrations and the histologic characteristics of the scar. Twenty-two animals were rebred 30 to 40 days after their cesarean sections. After repeat cesarean delivery, on day 19, the bursting pressure and hydroxyproline concentrations of the previous hysterotomy scar were determined. Results: The uterine horn bursting pressure in the GH-treated animals was significantly greater than that in the control animals both 28 days postpartum and near term in a subsequent pregnancy. The uterine hydroxyproline concentrations followed the same pattern. Histologic study of the scars showed they were thicker and had less cellularity in the treated animals than in the control animals. Conclusion: Postcesarean treatment with GH increased the bursting strength of rat uterine incisions. This effect was accompanied by a significant increase in collagen content and persisted through a subsequent pregnancy. (Am J Obstet Gynecol 2001;185:614-7.)

Interleukin-10 administration and bacterial endotoxin-induced preterm birth in a rat model

Objective: To determine whether intra-uterine infusion of interleukin-10 prevents preterm delivery in rats treated with endotoxin. Methods: Pregnant rats underwent implantation of uterine catheters and were randomly assigned to receive intrauterine infusion of either normal saline, 50 μg lipopolysaccharide endotoxin, or 50 μg lipopolysaccharide with 500 ng interleukin-10 administered either concurrently or 24 hours later. The interval from infusion to delivery for each group was recorded, along with the number of live born pups and their birth weight. We calculated that to obtain a power of 80%, assuming a 24-hour difference in the treatment to delivery times between the test and control subjects, at least six animals would be needed in each group. Results: In females receiving lipopolysaccharide (50 μg) alone, the interval to delivery ( P < .05), live birth rate ( P < .05), and pup weight ( P < .001) were reduced compared with the saline-infused controls. In contrast, females receiving interleukin-10 at the time of the endotoxin challenge or 24 hours after delivered at term with no difference in litter size or live birth weight compared with the controls. Conclusion: Animals treated with both lipopolysaccharide and interleukin-10, administered concurrently or 24 hours after the endotoxin challenge, delivered normal weight pups at term with a similar litter size as the saline-infused controls. Interleukin-10 appears to be effective in preventing endotoxin-induced preterm birth and fetal wastage in pregnant rats.

Use of osmotic minipumps for sustained drug delivery in rat pups: effects on physical and neurobehavioural development

Osmotic minipumps are often used as an alternative to repetitive injections for prolonged drug delivery in adult rats. The appropriateness of using this technology for sustained drug delivery in newborn rats, however, has not been validated. Our objective was to determine if implantation of osmotic minipumps, and the associated surgical stress, during a critical developmental period, affects early development and subsequent behaviour. SD rat pups were assigned to control, minipump, or sham surgery treatment conditions ( n=12/group). On P8, pups were briefly anaesthetised with isoflurane in oxygen, and Alzet 1007D osmotic minipumps, loaded with normal saline, were aseptically implanted (removed on P17). Sham-treated rats received identical treatment (with the exception of pump placement), while control pups were left undisturbed. Development was examined daily using a standard test battery (P9–P21), and learning and memory in pups was assessed in a T-maze (P15, P17 and P19). Weight (P27 and P72), open-field (P25, P26 and P27) and novel water maze performance (P60–P72) were examined in the resulting adult. With the exception of a transient decrease in weight gain, pump-treated animals did not differ from either sham or control rats, on any pre- or postweaning assessment. Based on these results we conclude that the use of osmotic minipumps in rat pups is a viable alternative to repeated injections for sustained drug delivery.

Changes in lipid peroxidation during pregnancy and after delivery in rats: effect of pinealectomy

Pregnancy is a physiological state accompanied by a high energy demand of many bodily functions and an increased oxygen requirement. Because of the increased intake and utilization of oxygen, increased levels of oxidative stress would be expected. In the present study, the degree of lipid peroxidation was examined in different tissues from non-pregnant and pregnant rats after the delivery of their young. Melatonin and other indole metabolites are known to be direct free radical scavengers and indirect antioxidants. Thus the effect of pinealectomy at 1 month before pregnancy on the accumulation of lipid damage was investigated in non-pregnant and pregnant rats after the delivery of their young. Malonaldehyde and 4-hydroxyalkenal concentrations were measured in the lung, uterus, liver, brain, kidney, thymus and spleen from intact and pinealectomized pregnant rats soon after birth of their young and at 14 and 21 days after delivery. The same parameters were also evaluated in intact and pinealectomized non-pregnant rats. Shortly after delivery, lipid oxidative damage was increased in lung, uterus, brain, kidney and thymus of the mothers. No differences were detected in liver and spleen. Pinealectomy enhanced this effect in the uterus and lung. It is concluded that during pregnancy high levels of oxidative stress induce an increase in oxidative damage to lipids, which in some cases is inhibited by the antioxidative actions of pineal indoles.

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model.

Previous pre-clinical studies with an anti-cocaine monoclonal antibody left open several issues critical to assessing the effectiveness of a vaccine for altering cocaine self-administration behavior. The objectives of this study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine. Two experiments were conducted using a second-order schedule of drug delivery in rats. The first was a passive-administration study using the anti-cocaine monoclonal antibody MO240 to examine the relationship between antibody level and cocaine self-administration behavior, and the second was an active-immunization study to examine the efficacy of the cocaine vaccine IPC-1010 for blocking various doses of self-administered cocaine. The passive-administration experiment with control and 4-mg or 12-mg MO240 treatments showed that antagonism of the 1 mg/kg cocaine training dose was dependent on antibody level. In animals whose serum antibody levels were sustained above 0.05 mg/ml, there was a sufficient amount of antibody to reduce drug-seeking behavior and drug intake. In the active-immunization experiment, the cocaine vaccine IPC-1010 induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of behavior by 1 mg/kg cocaine. Antagonism of cocaine self-administration after immunization was evident across a range of doses of cocaine and was only apparent in animals whose serum antibody levels exceeded 0.05 mg/ml. Furthermore, there was no evidence that the antagonism was surmountable within the dose range examined (up to 5.6 mg/kg). Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

Role of oxytocin in the initiation of term and preterm labor in rats: Changes in oxytocin receptor density and plasma oxytocin concentration and the effect of an oxytocin antagonist, L-366,509

Objective: Our purpose was to compare the functional roles of oxytocin in term and preterm labor in rats by both biochemical and pharmacologic means. Study Design: We determined the myometrial oxytocin receptor density and the maternal plasma concentrations of oxytocin and progesterone on gestational days 18, 20, and 22 (morning) and at the onset of delivery (day 22 afternoon) in rats with labor at term and at the onset of delivery (day 20 afternoon) in rats in preterm labor induced by the combined use of bilateral ovariectomy and estradiol injection. We also evaluated the effects of an oxytocin antagonist, L-366,509, on the initiation of both term and preterm labor. Results: The number of tritiated oxytocin binding sites in myometrial membranes rapidly increased on gestational day 22 (morning) in rats with term labor. Plasma progesterone level decreased in an inverse fashion. A rapid increase in circulating oxytocin concentration was observed at the onset of delivery in rats in labor at term. Both the plasma oxytocin concentration and the receptor density had the same values in rats with preterm labor as in rats with term labor. L-366,509 delayed the initiation of labor in rats with term and preterm labor in a dose-dependent manner. Conclusion: It is confirmed biochemically and pharmacologically that oxytocin plays an important role in the initiation of both term and preterm labor in rats. The oxytocin antagonist examined was able to delay term and preterm labor, so it might prove useful in clinical practice for the treatment of preterm labor. (Am J Obstet Gynecol 1999;180:621-7.)

Interaction of nitric oxide (NO) and progesterone on preterm delivery in rats

Interaction of nitric oxide (NO) and progesterone on preterm delivery in rats

Onapristone and prostaglandin E2 induction of delivery in the rat in late pregnancy: A model for the analysis of cervical softening

OBJECTIVES: Our purpose was to develop a method to induce premature delivery in rats and to use this method to identify biochemical changes that are critical to cervical dilatation by comparison to changes that occur during term delivery. STUDY DESIGN: Rats were treated with antiprogestational agents onapristone or lilopristone in combination with prostaglandin E2 or estradiol on day 19 of pregnancy to induce delivery before term. Mechanical and biochemical changes of the isolated cervix were compared with changes found at term and in 20-day controls. RESULTS: Rats treated with a combination of onapristone and prostaglandin E2 were consistently delivered 25 hours after treatment began. The physical characteristics of the cervix of treated rats changed to match those of term cervices. The ratio of the small sulfated proteoglycan (decorin) to collagen changed on induction to match the ratio found at term. CONCLUSIONS: This induction protocol can be used to advance the time of delivery in rats, with the further advantage that the time of delivery can be accurately predicted. The data strengthen a proposed model in which the interaction of decorin and collagen is an important determinant of the biomechanical properties of the cervix during pregnancy. (Am J Obstet Gynecol 1996;175:719-23.)

Oxytocin antagonists delay the initiation of parturition and prolong its active phase in rats

The physiological importance of oxytocin for the initiation and maintenance of labour and delivery is controversial. We investigated the effects of two novel peptide oxytocin antagonists on the onset and the progress of delivery in rats implanted with a jugular vein cannula one day before term. During delivery rats were given either an oxytocin antagonist (OVT16, n = 10, or F382, n = 7, 30 micrograms/kg) or vehicle (n = 10, 9) after the birth of the second pup and the time to deliver five more pups was recorded. Other rats were given an injection of F382 (30 micrograms/kg, n = 7) or vehicle (n = 9) after the birth of the fourth pup and the time to deliver three more pups was recorded. In another experiment rats were given repeated injections of F382 (30 or 60 micrograms/kg, n = 13, 11) or vehicle (n = 32) prepartum on the day of expected term and the time of onset and the progress of delivery was recorded. Rats given an antagonist after the second pup delivered the next five pups in 100 +/- 8 min (F382) and 83 +/- 12 min (OVT16), significantly slower than the respective controls (51 +/- 6 and 49 +/- 6 min, U-test, P < 0.05). Four of the 7 rats given F382 after the fourth pup showed no prolongation of delivery (time between pups 4-7: 24.7 +/- 2.9 vs 27.5 +/- 3.1 min in controls), while in the other three rats delivery was prolonged (time between pups 4-7: 86 +/- 4.3 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Antinociception and Side Effects of L and D Isomer Liposome-encapsulated Alfentanil after Spinal Delivery in Rats

Antinociception and Side Effects of L and D Isomer Liposome-encapsulated Alfentanil after Spinal Delivery in Rats

The role of loss of control and predictability in the hypoalgesic response to noncontingent food delivery in rats

Exposure to noncontingent food delivery has been shown to elicit an increase in nociceptive thresholds in food-deprived rats. In Experiment 1, we examined whether this hypoalgesic response might be attributed to a loss of control over food delivery. Rats were exposed to noncontingent food delivery with or without prior exposure to contingent food delivery, and nociceptive thresholds were recorded using the tail-immersion test. Both groups of rats exhibited significant increases in nociceptive thresholds, and no differences were found between rats that had experienced a loss of control and those that had not. In Experiment 2, we examined the role of predictability in the hypoalgesic response to noncontingent food delivery. Food-deprived rats were exposed to noncontingent food delivery with or without a light signal preceding the delivery of each food pellet. Both groups of animals exhibited significant increases in nociceptive thresholds. However, the hypoalgesic response was significantly reduced when food delivery was preceded by a light signal. These findings suggest that it is not merely a lack of control over food delivery which may be responsible for the activation of analgesic mechanism, but that the availability of predictability has an important modulatory role as well.

Liver-Directed Gene Therapy: Evaluation of Liver Specific Promoter Elements

Liver-directed gene therapy could dramatically alter the therapy of many inherited hematologic and metabolic diseases. We have developed a rapid, reliable, low-mortality method for the in vivo delivery in rats of retroviral vectors 24 hr after 70% hepatectomy by intraportal injection during hepatic in-flow occlusion (HIFO). Using the human α1-antitrypsin (hAAT) reporter gene, we found in vivo that up to 10% of hepatocytes integrated the provirus, and serum hAAT protein levels were sustained for up to 1 year. Despite high in vivo transduction efficiencies, gene expression at the mRNA level is disappointingly low compared to in vitro transduced NIH 3T3 or Hepa A 1 tissue culture cells. In this report, LNL-6-derived retroviral vectors (RV) were combined with one of two strong, liver-specific promoters, murine albumin or human α1-antitrypsin, an upstream insertion of a trimer of hepatocyte nuclear factor-3 (HNF-3) binding sites, and the hAAT reporter gene. HNF-3 has been demonstrated to increase in vitro transcriptional activity [23]. Twenty-four hours after 70% hepatectomy, 10-fold concentrated (by methotrexate-resistant titer) RV-producing cell supernatant was given intraportally during a 3-min HIFO. Serum hAAT levels as quantitated with a human specific ELISA were sustained for over 40 weeks with all of the liver-specific promoter constructions. However, the hAAT protein production with the murine albumin promoter retroviral constructs decreased with time, but was sustained at levels approximately 80% of the initial serum peak levels with the constructs containing the hAAT promoter. We conclude that the retroviral vectors containing liver-specific promoters can lead to sustained, transduced gene expression and the quantitative evaluation of in vivo promoter strengths is essential for the development of high expressing retroviral vectors necessary for hepatic gene therapy in humans.

Effects of peripheral nerve lesions during pregnancy on parturition in rats

Bilateral section of either the sensory or motor branch of the pelvic nerve or pudendal nerve was performed in rats on days 8-10 of pregnancy, and the effects on delivery were observed. Bilateral resection of the sensory branch of the pelvic nerve reduced the number of live pups per litter, and increased the number of stillbirths and the number of fetuses retained in utero per litter at day 24. Sectioning motor components of the pelvic nerve, or both motor and sensory components of the pudendal nerve, had no effects on delivery in rats. We conclude that of the peripheral nerves evaluated in this study, only the sensory branch of the pelvic nerve is required for normal vaginal delivery in this species.

Topical Effects of Absorption Enhancing Agents on the Rectal Mucosa of Rats in Vivo

In the present study, attempts have been made to assess the effects of cefoxitin formulations with various absorption promoters on mucosal integrity after rectal delivery in rats. Observations were made at 2 and 24h following drug administration. On macroscopic and histologic evaluation, all drug formulations affected mucosal structure in terms of hyperemia, edema, loss of goblet cell vacuoles, detachment of entero-cytes, and increase of the number of inflammatory cells; these effects were not reversible in 24h. The effects of formulations with MGK (a mixture of glyceryl-1-monooctanoate, glyceryl-1, 2-dioctanoate, glyceryl-1, 3-dioctanoate, glyceryl trioctanoate, glycerol, and octanoic acid), monoglycerides, 3-amino-1-hydroxypropylidene-1, 1-diphosphonate, and 4% (w/v) sodium tauro-24, 25-dihydrofusidate (STDHF) tended to exceed those observed with sodium salicylate, medium-chain fatty acids, Azone, and lower STDHF concentrations. The clinically used suppository bases Witepsol H15 and PEG 1540/6000 and indomethacin suppositories also affected mucosal structure. Although the interanimal variability in scores was very substantial, results indicate that rectal absorption enhancement is associated with modification of paracellular transport after detachment of enterocytes. However, the extent of drug absorption enhancement appeared not to be directly related to the extent of mucosal damage.