Pilot study with technosphere/PTH(1-34)--a new approach for effective pulmonary delivery of parathyroid hormone (1-34).

Sequential subcutaneous PTH injection therapy (repeated 14 days of PTH administration and a subsequent treatment pause for a few weeks) is known to increase bone mineral density in patients with osteopenic disorders. Alternative methods of drug delivery may be beneficial in increasing compliance. A pilot study was performed in 10 healthy volunteers (4 female/6-male, age: 25.6 +/- 3.5 years, BMI: 22.3 +/- 2.4 kg/m 2, mean +/- SD) to assess the pharmacokinetic profiles of 1600 IU of PTH(1 - 34) using the pulmonary Technosphere drug delivery system in comparison to a subcutaneous injection of 400 IU. The treatments were administered in the morning after an overnight fast and blood samples for measurement of PTH(1 - 34), PTH(1 - 84), and calcium and calcitonin were taken over a period of 6 hours. Both injection and pulmonary application of PTH(1 - 34) were well tolerated. After pulmonary administration of Technosphere/PTH(1 - 34), PTH(1 - 34) appeared in the serum with a faster concentration increase (T max: pulmonary 10 +/- 5 min vs. subcutaneous 28 +/- 8 min, p < 0.001) and with higher maximal concentrations (C max : pulmonary 309 +/- 215 pmol/l vs. subcutaneous 102 +/- 45 pmol/l, p < 0.05) as compared to the subcutaneous injection. The relative bioavailability of pulmonary Technosphere/PTH(1 - 34) was calculated to be 48 %. No differences were seen between pulmonary and subcutaneous application with regard to the PTH(1 - 84), calcitonin and calcium concentrations. In conclusion, pulmonary application of Technosphere/PTH(1 - 34) appears to be an effective and thus attractive candidate for PTH substitution therapy in osteoporosis and other conditions leading to a decrease in bone mineral density.

A self-complementary, self-assembling microsphere system: application for intravenous delivery of the antiepileptic and neuroprotectant compound felbamate.

Felbamate (FBM) is a novel antiepileptic drug (AED) and neuroprotectant (NP) compound that interacts with strychnine-insensitive (SI) glycine receptors in brain (IC(50) = 374 microM). FBM concentrations required to interact with SI glycine receptors are consistent with brain levels following oral and intraperitoneal administration of AED and NP doses. Because of the solubility limits of FBM, an intravenous (iv) form has not been developed. Nevertheless, an iv form could be important for the treatment of disorders such as status epilepticus and neuronal damage due to hypoxic/ischemic events. Substituted diketopiperazines precipitate in acid to form microspherical particles of uniform size ( approximately 2 microm). The microsphere system entraps drugs on precipitation and dissolves near physiological pH to release the drug cargo. Therefore, microspheres were used to produce an iv formulation of FBM. Mice were administered the FBM/microsphere (20-60 mg/kg FBM) and tested for protection against tonic extension seizures using maximal electroshock. The FBM/microsphere was effective in a time- and dose-dependent manner following iv administration. The median effective dose (ED(50)) for protection against MES seizures at 30 min was 27.2 mg/kg [95% confidence interval (CI) = 20.8-33.4, slope = 6.5]. The ED(50) for minimal motor impairment at 30 min was 167 mg/kg (95% CI = 155-177, slope = 28.1). Thus, the feasibility of encapsulating FBM or similar aqueous insoluble compounds in a microsphere system with delivery by the iv route for treatment of epilepsy and various central nervous system disorders has been clearly demonstrated. Studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals.

Cardiodynamic response to psychological and cold pressor stress: further evidence for stimulus response specificity and directional fractionation.

In the present study 36 police officers were exposed to a psychological stressor (IQ quiz) and to cold pressor stress while several cardiovascular variables were monitored. Impedance cardiography was used to provide measures of heart rate, stroke volume, cardiac output, myocardial contractility, and total peripheral resistance. In addition, measures of systolic and diastolic blood pressure and peripheral skin temperature were obtained. A multivariate analysis of variance (MANOVA) indicated that significant increases in diastolic and systolic blood pressure during the cold pressor test were mediated by large increases in total peripheral resistance, whereas blood pressure elevation during the IQ quiz were accompanied by significant increases in heart rate and, to a lesser extent, cardiac output. Peripheral skin temperature decreased in response to each stressor. Additional analysis indicated a degree of stimulus specificity for several variables. For example, diastolic blood pressure showed greater increases to cold pressor than quiz, whereas systolic blood pressure increased more with the psychological than the physical stressor. Directional fractionation occurred for both myocardial contractility and cardiac output.

Antihypertensive therapy and quality of life: a comparison of atenolol, captopril, enalapril and propranolol.

This randomized, double-blind parallel study compared the effects of atenolol, captopril, enalapril and propranolol in 360 men with mild-to-moderate essential hypertension. Patients were titrated until diastolic blood pressure (Korotkoff phase V) decreased by at least 10 mmHg or to 90 mmHg or less. Quality of life assessments, based on validated psychometric questionnaires and objective measurements of cognitive function, occurred after three study phases: placebo run-in (3-5 weeks), titration (1-4 weeks), and maintenance (4 weeks). After four weeks of maintenance therapy, atenolol, captopril and enalapril generally had equivalent effects on quality of life, as measured by psychometric questionnaires, whereas propranolol consistently evidenced worsening or less improvement. Global scores of distressing psychological symptoms differed as a function of specific treatment (P = 0.01), with improvements significantly better for the atenolol, captopril and enalapril groups as compared with the propranolol group. There were no statistically significant differences among treatments for changes in cognitive function at maintenance. Thus, the quality of life questionnaires differentiated among drugs of the same class, indicating that selection among antihypertensive drugs should be based on their specific qualities, not on general class characteristics.

Interactive effects of type A personality and psychological and physical stressors on human cardiovascular functions.

The first part of this study examined the relationship(s) between Type A behavior scores and heart rate, blood pressure and impedance derived cardiovascular measures in response to discrete stressors during a standardized psychophysiological assessment. Expts. 2A and 2B considered cardiovascular responses to dynamic exercise stress alone and in combination with psychological and cold pressor tests. Gender and stroke volume changes during the psychological stress correlated 0.45 (P less than 0.02) with Type A score. Subscale scores of Job Involvement correlated 0.78 (P less than 0.02) with stroke volume, total systemic resistance and heart rate during the psychological stressor, and systolic blood pressure during the cold pressor task. The combined effects of psychological stress and dynamic exercise on systolic and diastolic blood pressure were significantly greater than the individual effects of these stressors. The use of impedance cardiography in measuring cardiovascular variables that correlate with Type A behavior, during psychophysiological assessments, may further elucidate our understanding of Type A behavior in addition to providing information about how stress interacts with aerobic exercise.

Intracranial self-stimulation: temporal interactions among mesencephalic and diencephalic sites.

The monophasic pulse pair technique has been employed to ascertain whether pairs of intracranial self-stimulation (ICSS) sites interact with each other. The present study investigated the interactive properties of ICSS placements in the substantia nigra (SN) and mid-ventral periaqueductal gray (MV) with those hypothalamic ICSS placements within (MFB) or outside of (non MFB) the medial forebrain bundle. ICSS response rates when pulses of each pulse pair were split between two ICSS sites were significantly higher than the sum of rates when each site was stimulated singly with single-pulse trains. Moreover, all interaction conditions yielded higher rates than pulse pairs delivered to the mesencephalic site at an optimal interval, yet similar rates to pulse pair stimulation delivered to the diencephalic site. The symmetry of the interactions depended upon electrode loci: MV/MFB and SN/non MFB interactions were significantly higher when the mesencephalic site received the first pulse of each pair, effects which accounted for 49 and 58% of the variance respectively. Conversely, MV/non MFB and SN/MFB interactions were significantly higher when the mesencephalic site received the second pulse of each pair, effects which accounted for 5 and 14% of the variance respectively. These behavioral ICSS interactions are discussed in terms of interrelated heterogeneous subsystems subserving ICSS behavior.

Biofeedback efficacy studies: a critique of critiques.

Biofeedback, a field still in its infancy, has developed treatments that have been used with clinical success in the treatment of a number of disorders. Many have expressed their public concern that biofeedback had not lived up to its early promise and that it has not developed treatments that are, in fact, efficacious. A number of factors, which are inherent in biofeedback research, confound the results of clinical efficacy studies of biofeedback treatments. Researchers interested in the efficacy of biofeedback must address several issue: (1) Rejecting the null hypothesis is not equal to proving the null hypothesis (without the use of power analysis); (2) control for nonspecific effects is not equal to a double-blind experimental design; (3) ignorance of a mechanism of action is not equal to a lack of clinical efficacy; (4) the administration of training is not equal to the subject's learning to criterion; (5) untrained therapists are not equal to trained therapists; (6) statistical significance is not equal to clinical significance; and (7) the laboratory setting is not equal to the clinical setting.

Brain site variations in effects of morphine on electrical self-stimulation.

Pairs of bipolar electrodes were stereotaxically aimed at two of three sites: the locus coeruleus (LC), the substantia nigra, pars compacta (SNC), and the median forebrain bundle (MFB). Rats were shaped to bar-press for trains of intracranial electrical stimulation presented as pairs of monophasic pulses. The first pulse of a pair (the C, conditioning pulse) was followed by a second pulse (the T, test pulse) after a parametrically varied interval. The effects of chronic morphine administration were tested in a paradigm of 7 days saline, 7 days morphine, 1 day morphine+naloxone, and 6 days post-drug saline. High doses of morphine (5 mg/kg) depressed response rates for intracranial self-stimulation (ICSS). LC placements and those just lateral or ventral to the LC showed large increases in ICSS rates under morphine (2.5 mg/kg). This area was delimited on either side by tips that showed response rate depressions under morphine. MFB placements yielded response rate facilitations under morphine. Sites medial to the MFB and ventral within the MFB showed rate depressions under morphine. Dorsal substantia nigra placements showed facilitated rates, whereas placements ventral within the SNC and substantia nigra, pars reticulata (SNR) produced more variable results, with rates tending to be depressed by morphine. The ICSS procedure may be a useful animal model for detecting the abuse potential of drugs.

Morphine and intracranial self-stimulation in the hypothalamus and dorsal brainstem: differential effects of dose, time and site.

The purpose of this study was to examine if morphine, a drug of abuse, exerts site-specific effects on intracranial self-stimulation (ICSS). Rats, implanted with dorsal brainstem (DB) and hypothalamic (HYP) electrodes, bar-pressed for ICSS at two current intensities eight hours a day during six days each of predrug saline, morphine (2.5, 5.0, 7.5 or 10.0 mg/kg) and postdrug saline conditions. There were three patterns of drug effects: "pure" depressions, "pure" facilitations and a biphasic pattern (depressions followed by facilitations). Repeated morphine administration modified the temporal patterning of these effects: shortened duration of depressions and produced earlier onsets of facilitations. Within an animal, DB electrodes displayed more depressions than the HYP electrodes. Tolerance to the depressant effects, observed frequently, occurred occasionally to the facilitative effects of morphine. The drug effects on ICSS were dissociated from those observed on other behavioral measures, and thus are not artifacts of concomitant changes in activity levels.

Intracranial self-stimulation site specificity: the myth of current spread.

Locus-specificity of intracranial self-stimulation (ICSS) was determined for 78 electrode placements using monophasic stimulation. ICSS rate comparisons between each pole of a bipolar electrode when each served as cathode were made when the anodal source was either the other pole of the bipolar electrode or a skull screw. In hypothalamic areas, medial forebrain bundle electrode tips elicited significantly higher rates than electrode tips of the same bipolar electrodes located in perifornical or far-lateral diencephalic placements. In turn, perifornical electrode tips elicited higher rates than more dorsally or medially placed tips. In dorsal pontine areas, locus coeruleus electrode tips elicited significantly higher rates than more medially or laterally placed tips. In periaqueductal midbrain and substantia nigra placements, tips located along the midline or in the substantia nigra elicited significantly higher rates than tips located lateral to or ventral to those respective structures. Anodal locus did not change these results. These results suggest that ICSS behavior is delimited by and corresponds to neuroanatomically discrete entities and that cathodal, rather than anodal factors seem to most crucially determine ICSS integrity.

Stress-produced analgesia and morphine-produced analgesia: lack of cross-tolerance.

Animals exposed to cold-water swims, rotation, inescapable shocks, abrupt food deprivation and other stressors display temporary analgesia. Since repeated exposures result in adaptation of this analgesia in much the same way that repeated administration of opiates results in tolerance, the possibility of cross-tolerance between cold-water stress-induced and morphine-induced analgesia was investigated. Flinch-jump thresholds were determined in ten experimental groups of six rats each. Three groups showed dose-dependent analgesia following single injections of morphine at 5, 10 and 15 mg/kg, respectively. A fourth group, subjected to a single cold-water swim at 2 degrees C for 3.5 min, displayed analgesia comparable to that produced by 10 mg/kg of morphine. Groups subjected either to 14 daily cold-water swims or to 14 daily morphine injections at 10 mg/kg showed normal thresholds on the 14th day indicating that adaptation and tolerance had developed, respectively. The cross-over groups were exposed to either 13 days of could-water swims followed by morphine or the reverse arrangement. Both groups showed profound analgesia instead of cross-tolerance, suggesting that a non-opiate neural mechanism may mediate stress-induced analgesia.

Characterization of self-stimulation elicited from rat dorsolateral pariaqueductal gray.

Rats were stereotaxically implanted with chronic bipolar electrodes aimed at the periaqueductal central gray (PCG) and were subsequently tested for intracranial self-stimulation (ICSS) behavior. Consistent and reliable ICSS behavior was elicited from both the midventral and dorsolateral portions of the PCG, the latter result occurring in loci previously reported as predominantly aversive. Midventral PCG ICSS rates were significantly higher than dorsolateral PCG ICSS rates. The higher rates were not accounted for by either current intensity used or motor artifacts. Moreover, both sites displayed reliable ICSS behavior characterized by regular low-variability rates and no seizure activity, seen with other brainstem ICSS sites, but unlike diencephalic and telencephalic ICSS behavior which is characterized by irregular bursts of responding which are highly variable and sometimes accompanied by seizures. The differential ICSS responsivity between PCG structures suggests that they may be mediated by different anatomically-localizable substrates.

Alteration of escape from rewarding electrical brain stimulation by D-amphetamine.

Rats were trained both to barpress for and escape from locus coeruleus, midbrain periaqueductal gray and hypothalamic stimulation. Rate-intensity functions for intracranial self-stimulation (ICSS) behavior and latency-intensity functions for escape behavior were obtained for each electrode site in each animal. Following baseline, d-amphetamine was administered and responding was compared with the saline condition for both rate-intensity and latency-intensity functions. ICSS response rates were enhanced by d-amphetamine at all loci, particularly at threshold intensities, while escape responding was biphasically affected by d-amphetamine at all loci. D-amphetamine increased escape latencies at intensities which, under saline, elicited short escape latencies, while decreasing escape latencies at intensities which, under saline, elicited long escape latencies. A significant correspondence was noted between intensities which, under the influence of d-amphetamine, both elicited longer escape latencies and higher ICSS response rates, suggesting that in both ICSS and escape paradigms, animals were titrating the duration of the stimulus train. No site-specific effects of d-amphetamine upon escape behavior were noted.

Comparison of behaviors elicited by electrical brain stimulation in dorsal brain stem and hypothalamus of rats.

Four brain-stimulation phenomena elicited from both dorsal brain stem and hypothalamic sites were investigated with the following results: (a) intracranial self-stimulation rate-intensity functions for dorsal brain stem and hypothalamic sites yielded very high (over 1,000 responses/15 min.) to moderate (201-500 responses/15 min.) response rates; (b) d-amphetamine produced higher response rates than either l-amphetamine or saline at both dorsal brain stem and hypothalamic sites, indicating that noradrenergic dorsal brain stem fibers (or cell bodies) support intracranial self-stimulation; (c) dorsal brain stem and hypothalamic self-stimulation sites reliably produced escape behavior; (d) simultaneous stimulation of dorsal brain stem and hypothalamic sites at subthreshold intensities interacted to produce suprathreshold response rates.