Overt Side Effects Research Articles

The Effect of Long-Term Antipsychotic Treatment on Prolactin

This naturalistic, cross-sectional study was designed to assess the risk of prolactin level elevation and associated side effects in youths taking long-term atypical antipsychotic medication. Subjects were enrolled from outpatient child psychiatric treatment settings in upstate New York who were taking risperidone, olanzapine, or quetiapine for at least 6 months. Demographic data, medication history, and side effects were elicited at the initial interview. Two fasting morning serum prolactin levels were obtained 1 month apart, and the results were averaged. Fifty outpatient youths, with a median age of 13 years, were enrolled in the study. The median overall duration of use of an atypical antipsychotic was 22.1 months. The median dose of medication for risperidone was 1.5 mg/day, for olanzapine 10 mg/day, and for quetiapine 200 mg/day. The mean prolactin level among all patients on risperidone was significantly greater than controls, as well as for those on quetiapine or olanzapine. The risk of hyperprolactinemia with long-term use of risperidone appears to be significantly greater than for olanzapine or quetiapine. Overt side effects were infrequent in the overall sample, but serum prolactin assessment is recommended for youths taking risperidone chronically. Because of variability found in sequential prolactin samples, repeat samples may be warranted.

The role of CD40-CD154 interaction in cell immunoregulation.

CD40, a member of the nerve growth factor/tumor necrosis factor receptor superfamily, and its ligand, CD154, play essential roles in cell immune responses. The results of many studies have indicated that CD40-CD154 interaction can upregulate costimulatory molecules, activate antigen-presenting cells (APCs), influence T-cell priming and T-cell-mediated effector functions as well as participate in the pathogenic processing of chronic inflammatory diseases, such as autoimmune diabetes, graft rejection, atherosclerosis, and cancer. Ligation of CD40 on cancer cells was also found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptosis with no overt side effects on normal cells and treatment with CD154 can heighten tumor rejection immune response as well. However, systemic treatment with CD154 has some potential risks. Therefore, searching for efficient and safe strategies of CD154-based cancer therapy has been a hot topic in human cancer research. This review focuses on the latest discovered functions of CD40-CD154 interaction in cell immune responses and on the new findings of CD154-based human cancer therapy.

Prospects for CD40-directed experimental therapy of human cancer.

CD40, a member of the tumor necrosis factor receptor (TNF-R) family, is a surface receptor best known for its capacity to initiate multifaceted activation signals in normal B cells and dendritic cells (DCs). CD40-related treatment approaches have been considered for the experimental therapy of human leukemias, lymphomas, and multiple myeloma, based on findings that CD40 binding by its natural ligand (CD40L), CD154, led to growth modulation of malignant B cells. Recent studies also exploited the selective expression of the CD40 receptor on human epithelial and mesenchymal tumors but not on most normal, nonproliferating epithelial tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small cell lung, and squamous epithelial carcinoma cells was found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptotic induction with no overt side effects on their normal counterparts. CD154 treatment also heightened tumor rejection immune responses through DC activation, and by increasing tumor immunogenicity through up-regulation of costimulatory molecule expression and cytokine production of epithelial cancer cells. These immunopotentiating features can produce a "bystander effect" through which the CD40-negative tumor subset is eliminated by activated tumor-reactive cytotoxic T cells. However, the potential risk of systemic inflammation and autoimmune consequences remains a concern for systemic CD154-based experimental therapy. The promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell growth, and indirectly activate antitumor immune response, may depend on selective and/or restricted CD154 expression within the tumor microenvironment. This may be achieved by inoculating cancer vaccines of autologous cancer cells that have been transduced ex vivo with CD154, as documented by recently clinical trials. This review summarizes recent findings on CD154 recombinant protein- and gene therapy-based tumor treatment approaches, and examines our understanding of the multifaceted molecular mechanisms of CD154-CD40 interactions.

Antagonists of GLU(K5)-containing kainate receptors prevent pilocarpine-induced limbic seizures.

Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.

Achieving genetic potential for nutrition and growth in cystic fibrosis

Achieving genetic potential for nutrition and growth in cystic fibrosis

28-day toxicology test: indenopyridine RTI 4587-056 in male Sprague–Dawley rats☆

The potential toxicity of RTI 4587-056, a hexahydroindenopyridine analog of SANDOZ 20-438, was examined in adult male Sprague–Dawley rats. Testicular, intestinal, and erythropoietic histology was assessed after 28 days of gavage treatment at 0, 10, and 100 mg/kg/day. During the first 10 days, dose-related clinical signs included mild to moderate lethargy shortly after dosing, lower consumption of feed and water, and body weight loss or decreased weight gain. Tolerance developed, such that lethargy disappeared and weight gains were equivalent to the control group during the second through fourth weeks. The compound did not affect intestinal epithelium or bone marrow. RTI 4587-056 was a highly effective antispermatogenic agent at both doses causing epididymal hypospermia and testicular atrophy. Based upon the Spermatogenic Index ratings, still lower doses would be effective male contraceptive agents. RTI 4587-056 has potential as a male contraceptive without overt side effects. Further testing is required.

Behavioral effects of apamin, a selective inhibitor of the SK Ca-channel, in mice and rats

Apamin, a highly selective and potent peptide that blocks the SK Ca-channels has been suggested to be a cognition enhancer. We tested apamin in the Morris water escape task, in shock motivated avoidance tasks, and in operant tasks in the Skinnerbox. We also used non-cognitive tests, such as the rat forced swimming test and cocaine-induced locomotor activity in the open field, and a test to assess the side effect profile. Mice and rats from different strains, and rats of different ages were used. The rat studies provided only weak support for the notion that apamin acts as a cognition enhancer. More convincing evidence was obtained from the mouse studies. Overt side effects of apamin were found at the dose of 0.3 mg kg −1. This dose was close to, or even overlapped, the doses which improved cognition in mice. We conclude that apamin is a poor tool to assess the role of SK Ca-channels in learning and memory processes.

Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia

Cyclosporin A (CsA) reduces ischemic brain damage when administered in such a way that its penetration across the blood–brain barrier is enhanced. Since only pretreatment has previously been used in focal ischemia, the objective of the present study was to establish whether posttreatment is efficacious and to assess the window of therapeutic opportunity for CsA. To that end, CsA was given 5 min to 6 h after the start of reperfusion following 2 h transient ischemia, and infarct volume was assessed after 48 h by triphenyltetrazolium chloride staining. Attempts were made to circumvent the BBB to CsA by an intracerebral needle lesion, by an increase in the intravenous CsA dose, or by osmotic opening with intracarotid mannitol. The results were compared to those obtained with FK506. Intravenous CsA in a dose of 10 mg/kg failed to reduce infarct volume, unless preceded by a needle lesion. That procedure, and an increase in CsA dose to 50 mg/kg, reduced infarct volume to about 50% of control, but the higher dose had toxic side effects. The coupled intracarotid infusion of mannitol and CsA (10 mg/kg) was more efficacious, without overt side effects. However, mannitol proved dispensable since CsA alone reduced infarct volume to 30% of control, with a therapeutic window of 3–6 h. When given after 5 min of reflow, CsA reduced infarct volume to 10% of control and was clearly more neuroprotective than FK506. Possibly, this is because CsA blocks the mitochondrial permeability transition pore which is opened under adverse conditions.

Reduction of motoric agitation and restlessness by AF102B and tacrine in the macaque.

The cholinesterase inhibitor tacrine (THA) and the M1 muscarinic agonist AF102B (cevimeline), both reported to enhance cognition in animals and humans, were tested in 5 macaques for reduction of spontaneous, random movements. Monkeys were videotaped 1 hour after administration of normal saline vehicle, after low- and high-dose intramuscular AF102B, and after low- and high-dose oral THA. Two independent blind judges counted numbers of spontaneous movements made by each monkey over 12 consecutive 15-second segments for each drug condition. Both THA and AF102B reduced movement significantly at high doses without overt side effects, warranting further research on the agitation-reducing potential of cognition-enhancing cholinomimetic drugs.

Glucagon-like peptide-1: a potent regulator of food intake in humans

Background/AimsStudies in animals suggest a physiological role for glucagon-like peptide-1-(7–36)-amide (GLP-1) in regulating satiety. The role of GLP-1 in regulating food intake in man has, however, not been investigated.Subjects—Sixteen healthy...

Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

Stereotactic radiosurgery of the rat dunning R3327-AT1 prostate tumor

Stereotactic radiosurgery (RS) is being used increasingly for the treatment of small benign and malignant lesions, particularly in the brain. However, to fully realize the potential of this technique, more experimental data are needed. In this report we describe an RS technique suitable for small animals, and present the results obtained with different irradiation doses and volumes given to a rat prostate tumor. Single doses of RS were administered to the Dunning prostate R3327-AT1 carcinoma transplanted subcutaneously into the thigh of male Copenhagen rats. The tumors (approximately 5 mm in diameter) were localized within a stereotactic frame and irradiated at a linac facility (15 MV) with single doses of 15.3, 30.6, 46.0, 61.3, or 76.6 Gy at the 80% isodose level using narrow beams from 3- and 5-mm collimators (80% isodose field size of 5 or 8.5 mm, respectively) and a six-arc irradiation technique. Tumor size was measured three times a week (Mondays, Wednesdays, and Fridays). Conventional stains were used to examine the histologic status of the tumors. To evaluate the proliferative response of the tumors to RS and assess the prevalence and spatial distribution of proliferating cells, tissue slices were stained with the proliferation markers 5-bromo-2'- deoxyuridine and proliferating cell nuclear antigen 4 and 8 h, and 4, 8, 12, and 210 days after stereotactic irradiation with a dose of 61.3 Gy. The extent of growth delay and local tumor control depended on the radiation dose, the field size, and the accuracy of irradiation. Local control at day 100 ranged from two of eight rats at 30.6 Gy, five of seven rats at 61.3 Gy, and six of seven at 76.6 Gy. No overt side effects in the surrounding tissues was observed. After 61.3 Gy, the immunohistochemical staining revealed a rapid decrease of proliferative active tumor cells after irradiation. The irradiated tumor tissue was gradually replaced by connective tissue. However, in one persistent nodule, a few proliferative cells were detected even after 200 days. A radiosurgical technique was successfully developed for a small animal system. The technique was concluded to be reproducible and suitable for future use in single and fractionated treatment regimens.

Vaccination for contraception.

Vaccination for birth control has several advantages over currently available methods of family planning and should prove an attractive addition to the contraceptive armamentarium both in developing countries and in a developed country such as Australia. Concerns have been voiced by consumer health advocates that vaccines, like other long acting contraceptive methods, may be abused by health authorities in developing countries and by their use in vulnerable groups such as aborigines in our own country. These concerns need to be recognised and addressed. More difficult to accommodate are the anxieties expressed by feminist groups about the 'loss of control' and 'lack of body awareness' inherent in a method, such as a vaccine, that is relatively easily administered and has no overt side effects. There is no evidence that these concerns are shared by women in general. The antifertility vaccine that will most likely be applied first in family planning programmes is one directed against the pregnancy hormone hCG. A WHO vaccine directed against the C-terminal peptide of beta-hCG provokes a specific and safe immune response and will enter Phase 2 trials in Sweden this year. Subsequent developments with this vaccine will include the replacement of the current emulsion vehicle by a delivery system based on biodegradeable microspheres which will give a more sustained antigen release and duration of effectiveness.

Effect of intravenous human gastrin-releasing peptide on food intake in humans

Background/Aims: Bombesin and gastrin-releasing peptide (GRP) are closely related peptides. Both have been proposed to serve as a satiety signal in animals. Methods: To explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions. Results: GRP produced a significant reduction in calorie intake (P < 0.05) but only a 19% (nonsignificant) reduction in food intake. Fluid ingestion was not affected by GRP. No overt side effects were produced by GRP, but subjects experienced less hunger and early fullness in the premeal period during GRP infusion but not when receiving saline (P < 0.05−0.01). Conclusions: This study shows that intravenous infusions of GRP can decrease spontaneous food intake at concentrations that produce physiological effects, such as stimulation of acid or pancreatic secretion or gallbladder contraction. The data imply that GRP-like peptides can act as satiety signals in humans, confirming data previously reported in animals.

Histomorphometrical analysis of the effects of the bisphosphonate alendronate on bone loss caused by experimental periodontitis in monkeys.

This study tested the efficacy of alendronate, a bisphosphate, in reducing alveolar bone loss caused by experimental periodontitis in cynomolgus monkeys. Periodontitis was initiated in adult monkeys by ligating mandibular molar teeth at the cementoenamel junction (CEJ) and subsequently inoculating the ligature with Porphyromonas (Bacteroides) gingivalis. Contralateral, homologous non-ligated teeth served as controls. Animals received, intravenously, either saline (placebo) or alendronate at 0.05 or 0.25 mg/kg every 2 weeks for 16 weeks. After the animals were sacrificed, coronal sections through mandibular molars were subjected to histomorphometrical analysis. No overt side-effects were observed in any of the animals participating in this study. In placebo-treated animals, ligation and inoculation resulted in significant bone loss both at the CEJ and at the furcation. Alendronate at 0.05 mg/kg significantly reduced bone loss associated with the experimental periodontitis at both sites. In contrast, the dose of 0.25 mg/kg was ineffective in attenuating alveolar bone loss in the furcation area and only slightly effective in preventing it at the CEJ area. The results of the histomorphometric analysis correlate closely with those of the radiographic analysis of the same experiment. These data indicate that alendronate could reduce the loss of alveolar support associated with periodontitis and suggest that bisphosphonates, by virtue of their significant inhibitory action on osteoclasts, may become a treatment modality in the battle against alveolar bone destruction during periodontal disease.

Intravenous infusion of bombesin reduces food intake in humans.

Infusion of bombesin into healthy young men at two dosages (1.33 and 4.0 ng.kg-1.min-1) resulted in a significant 135-g reduction in intake of a yogurt and fruit blend, compared with saline infusions, at the higher dose, but only a 20-g (nonsignificant) reduction at the lower dose. There were no overt side effects, although half of the subjects reported a slightly elevated (mean elevation = 0.5 on a 1-5 category scale) sick sensation when receiving bombesin at the higher dose, but not when receiving saline. At the higher dose, the mean palatability of the test meal was reduced by 0.5 units on a nine-point scale of liking. This study demonstrates for the first time in humans that a slow intravenous infusion of bombesin can decrease spontaneous food intake when infused at the rate of 4 ng.kg-1.min-1 beginning at the onset of a meal. These results confirm that the short-term satiety effect of peripherally administered bombesin previously reported in animals can be obtained in humans.

Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia

Pantethine (P), the stable disulphate form of pantetheine, major component and precursor of coenzyme A, was evaluated within a double-blind protocol (8 weeks for P or for a corresponding placebo) in 29 patients, 11 with type IIB hyperlipoproteinemia, 15 with type IV, and 3 with an isolated reduction of high density lipoprotein cholesterol (HDL-C) levels. In type IIB patients, P (300 mg t.i.d.) determined a highly significant lowering of plasma total and low density lipoprotein (LDL) associated cholesterol (−13.5% for both parameters). In the same patients, HDL-C levels increased about 10% at the end of treatment. Switching from P to placebo was associated with a rapid return to the baseline cholesterolemia. Both in type IIB and type IV patients, plasma triglyceride levels were reduced around 30%, when P was given as the first treatment; when it was preceded by placebo, reductions were less striking (respectively, −17.8% for type IIB and −13.0% for type IV, at the end of P treatment). HDL-C levels were not increased by P, either in type IV, and in the patients with low HDL cholesterolemia. In type IV, LDL cholesterol levels showed a variable response to P: they tended to increase when below 132 mg/dl, prior to treatment, and to be reduced when above this level. This study provides evidence for a significant hypocholesterolemic effect of P, a natural compound free of overt side effects. It also indicates that P may raise HDL-C levels in type IIB patients, while moderately reducing triglyceridemia.

C-Terminal octapeptide of cholecystokinin decreases food intake in obese men

Six of eight obese men ate significantly less food during an intravenous infusion of the C-terminal octapeptide of cholecystokinin (CCK-8, 4 ng·kg −1·min −1) than during a saline infusion in a double blind experimental paradigm. Subjects stopped eating sooner during CCK-8. CCK-8 did not change the rate of eating. No overt side effects were reported or observed. This is the first report of the satiety effect of CCK-8 in obese humans and it suggests that the therapeutic potential of CCK-8 for the treatment of obesity deserves investigation.