β-Phenylethylamine and various monomethylated and para-halogenated analogs. Acute toxicity studies in mice.

Phenylethylamine's acute toxic effects in a population of adult (10 to 12 weeks old; ∼30 g) Swiss male albino mice are significantly increased by para-position aromatic ring halogenation. LD, LD, and LD values (mg/kg; x ± SEM) for p-F- (116.7 ± 3.

Behavioral effects of β-phenylethylamine and various monomethylated and monohalogenated analogs in mice are mediated by catecholaminergic mechanisms.

The effects of the administration [intraperitoneally, 15 and 75 mg/kg, except α-MePEA (amphetamine, AMPH) at 5 and 10 mg/kg] of β-phenylethylamine (PEA), its methylated (o-Me-, p-Me-, α-Me-, β-Me-, N-Me-, p-OMe-, N,N-di-Me-, and 3,4-diOH-N-Me-), para-halogenated (Br-, Cl-, F-, and I-), and other derivatives for example, p-OHPEA (p-tyramine), on Swiss male albino mice caged behavior fall into 3 broad categories. (1) N,N-diMe-, 3,4-diOH-N-Me-, and o-MePEA tend to reduce the behavioral activity, (2) p-OH and p-IPEA were without noticeable effects, and (3) the remaining compounds increased locomotor activity, produced hyperexcitability and fighting, jumping and vocalization, and convulsion in a graded manner (listed in increasing order p-OMe-, β-Me-, p-Cl-, p-Br-, p-F-, p-Me-, and N-MePEA, PEA itself and α-MePEA). The latter compound (amphetamine) being the most potent among them; equieffective but with lower potency were p-MePEA, N-MePEA, and PEA itself.

Analgesic effects of β-phenylethylamine and various methylated derivatives in mice.

Administration of β-phenylethylamine (PEA), the simplest endogenous neuroamine, and various methylated PEA derivatives including α-methyl PEA (amphetamine, AMP) elicits analgesia in mice. Five or 20 min after intraperitoneal PEA injection of as little as 6 mg/kg resulted in an increased latency response time (from 2.4 ± 0.

A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension.

The magnitude of increase in systolic blood pressure in response to the shift from supine to upright posture is considered to reflect the adequacy of orthostatic regulation. Orthostatic integrity is largely maintained by the interaction between the skeletal muscle pump, neurovascular compensation, neurohumoral effects, and cerebral blood flow regulation. Various physiological states and disease conditions may disrupt these mechanisms as seen in vasovagal syncope, dysautonomic orthostatic intolerance, and postural orthostatic tachycardia syndrome.

Rat brain-uptake index for phenylethylamine and various monomethylated derivatives.

Phenylethylamine and its monomethylated derivatives p-methylphenylethylamine, α-methylphenylethylamine, phenylethylamine itself, N-methylphenylethylamine, o-methylphenylethylamine, and β-methylphenylethylamine, readily cross the blood-brain barrier showing a brain-uptake index (%) ± SD (water considered 100 %), of 108 ± 11, 98 ± 14, 83 ± 6, 78 ± 11, 62 ± 7 and 56 ± 6, respectively (injection of tritiated water and 100 μg standard amine, which was measured by gas-liquid chromatography). Similar brain-uptake index values (determined by double isotope counting) were obtained for phenylethylamine and α-methylphenylethylamine (amphetamine) after the injection of tritiated water and C(14)-labeled amine (either 3 μg or when added 100 μg standard compound), suggesting that they entered the brain via passive diffusion. Accordingly, both amines distributed rather evenly in the various rat brain areas examined: uptake index (%) ± SD (double isotope counting; non-, and diluted labeled amine) for phenylethylamine (89 ± 8 and 78 ± 7, 83 ± 9 and 86 ± 9, 96 ± 6 and 84 ± 7) and for α-methylphenylethylamine (88 ± 11 and 87 ± 9, 93 ± 14 and 87 ± 11, 97 ± 12 and 87 ± 9) for the cerebellum, frontal cortex, and striatum, respectively.

Changes in plasma methionine-enkephalin levels associated with a cluster headache episode.

Eighteen male cluster headache (CH) inpatients within a CH series participated in this research. Blood samples were drawn from patients at least 6-hour pain-free after the last acute CH episode and then shortly prior (SP), during, and soon after (SA) a new acute CH attack. Three healthy male, age-comparable drug-free volunteers served as controls; 5 samples were obtained from each of these individual over a 24-hour period.

Decreased plasma methionine-enkephalin levels in cluster headache patients.

Results from a longitudinal study (blood drawn at days 29, 64, 89,124, 142, and 182 of the protocol) shows that the concentration of platelet-poor plasma (PPP) methionine(5)-enkephalin (MET) in healthy, drug-free, white male individuals (n = 5) remains within a relatively narrow range, well within the experimental error of the analytical procedures used. Interindividual differences fail to reach statistical significance [x ± SD and range (MET picograms per mL of PPP) of 91.2 ± 15.

A review of orthostatic blood pressure regulation and its association with mood and cognition.

Aims: This paper will review literature that examines the psychological and neuropsychological correlates of orthostatic blood pressure regulation.

Results: The pattern of change in systolic blood pressure in response to the shift from supine to upright posture reflects the adequacy of orthostatic regulation. Orthostatic integrity involves the skeletal muscle pump, neurovascular compensation, neurohumoral effects and cerebral flow regulation.

Biological correlates of migraine and cluster headaches: an overview of their potential use in diagnosis and treatment.

Current diagnostic criteria for headaches are based on the International Classification for Headache Disorders, second edition, which is largely built on data obtained from clinical examinations and patients' medical histories. Despite decades of vigorous basic and clinical research, we still lack reliable clinical laboratory diagnostic markers for headaches, which clearly obstructs the physician's ability to optimize and follow the patient's response to treatment protocols as well as holds back the discovery and implementation of new therapeutic modalities. In this paper, we review and discuss current efforts to identify and characterize biochemical and immunological changes in biological fluids and tissue that may be specifically associated with the etiology and/or pathophysiology of migraine and cluster headaches; we also discuss some of the recent genetic findings and ion channel modulation studies that may help to distinguish among various headache populations.

Degradation kinetics of methionine5-enkephalin by cerebrospinal fluid: in vitro studies.

Changes in the levels or biochemistry of cerebrospinal fluid (CSF) neuropeptides with opioid-like properties have been suggested to reflect alterations in specific biological processes. We have determined various kinetic parameters for methionine-enkephalin (MET) degradation by CSF samples from nonneurological patients. Study subjects included 9 males (51-67 years of age) and 5 females (47-61 years of age).

Bacitracin-sensitive aminopeptidase(s) degradation of methionine(5)-enkephalin by human brain putamen and hippocampus preparations: inhibition by phenothiazine drugs.

Select phenothiazine drugs significantly decrease, in a dose-dependent manner, the rate of methione-enkephalin (MET) degradation by discrete human brain areas, for example, putamen and hippocampus. This pentapeptide is rapidly, and essentially completely, hydrolyzed at the tyrosine-glycine bond by bacitracin-sensitive aminopeptidase(s) (AP); neither dipeptidyl peptidase(s) (N-carboxyphenylmethyl leucine and captopril) nor peptidyl dipeptidase(s) (thiorphan) inhibitors altered the kinetics of MET degradation. Half-life (t1/2) and initial velocity (Iv) of this reaction were significantly increased and decreased, respectively, by fluphenazine > prochlorpherazine > chlorpromazine > thioridazine > promethazine > ethopropazine; brain A hippocampus (t1/2, control 2.

Etiology and risk factors for developing orthostatic hypotension.

Orthostatic hypotension (OH) is regarded as a decrease primarily in systolic blood pressure on changing position from supine to erect. Based on clinical criteria, it is characterized by a decrease in systolic pressure of 20 mmHg and diastolic pressure of 10 mmHg within 1 to 3 minutes of standing after being supine. It is most prevalent in, although not limited to, the elderly population and is characterized by a variety of problems, including diminished cognition and disturbed emotion along with gate problems, falls, and brain and cardiovascular difficulties.

Degradation kinetics of methionine5-enkephalin by select brain areas from patients with chronic schizophrenia.

After 10-minute incubation of [3H]-tyrosine methionine-enkephalin (MET) with 100,000 x g supernatant from select brain regions of patients with chronic schizophrenia (n = 3), essentially all of the labeled tyrosine was recovered as the free amino acid. Initial velocity and half-life of MET degradation obtained from different brain areas (limbic system, thalamus, basal ganglia, cerebellum, and cortex) of individual brains or from equivalent sections from different brains were scattered and considerable spread out (brains A, B, and C: 21.7-60.

In vitro methionine5-enkephalin degradation kinetics by human brain preparations.

Incubation of [3H]-tyrosine methionine5-enkephalin (MET) with human brain preparations (100,000g supernatant; sections of the limbic system, thalamus, basal ganglia, cerebellum, and cortex) results in its rapid and complete degradation; over 95% of the initial labeled tyrosine is recovered as the free aminoacid within 10 min. Results show a considerable range in the peptide initial velocity (Iv) and half-life (t1/2) degradation values obtained from different brain sections of individual brains, either from the same or from different main brain areas. This relatively wide range of values was scattered, failing to identify consistent differences between the various brains areas studied.

Phenothiazine molecule provides the basic chemical structure for various classes of pharmacotherapeutic agents.

The chemical structure of phenothiazine provides a most valuable molecular template for the development of agents able to interact with a wide variety of biological processes. Synthetic phenothiazines (with aliphatic, methylpiperazine, piperazine-ethanol, piperazine-ethyl, or piperidine side-chain) and/or phenothiazine-derived agents e.g.

Inhibition of human plasma leucine5-enkephalin aminopeptidase hydrolysis by various endogenous peptides and a select number of clinically used drugs.

We identified a number of clinically used drugs and biologically active endogenous peptides able to significantly decrease the rate of human plasmatic aminopeptidase (AP) leucine-enkephalin (LEU) degradation. Bacitracin, bestatin, fluvoxamine, and each of 4 peptides tested significantly increased, in a dose-dependent manner (10-10 M), LEU degradation half-life (t1/2) in each of 5 plasma samples studied. Each sample was obtained by pooling equal volume of 6 randomly selected, individual plasmas (4 male and 2 female healthy, drug-free volunteers).

Human natural killer cell lysis of Salmonella typhi intracellularly-infected U937 cells.

Peripheral blood mononuclear cell (PBMC) cytotoxicity against S. typhi (wild type or mutant strain TYT1231)-infected U937 cells was significantly higher than its lytic effect against noninfected cells (control) at the various effector-to-target cell ratio used (30:1, 50:1 and 70:1). Natural killer cell activity [expressed as % specific lysis (mean +/- SEM); 30:1 (25.

Lysis of salmonella typhi intracellularly infected U937 cells by human natural killer cells: effect of protein kinase inhibitors.

We examined the effect of Salmonella typhi (wild-type Ty2 and mutant strain TYT1231)-infected U937 cells on natural killer cell (NKC) cytotoxicity of peripheral blood mononuclear cells (PBMCs) and highly purified NKC (HPNKCs; CD16(+)/CD56(+) > 95%; the rest corresponding to CD3(+) T cells). We also analyzed the possible role of various protein kinases involved in natural cytotoxicity on these processes. PBMC cytotoxicity against S typhi-infected U937 cells was significantly higher (paired Student t test; P < 0.

In vitro human plasma leucine(5)-enkephalin degradation is inhibited by a select number of drugs with the phenothiazine molecule in their chemical structure.

A number of drugs with the phenothiazine molecule in their chemical structure inhibit in a dose-dependent manner human plasmatic aminopeptidase leucine(5)-enkephalin (LEU) metabolism. Half-life peptide degradation was significantly increased by thioridazine > fluphenazine > As-1397 [10-(alpha-diethylaminopropionyl)phenothiazine] >/= promethazine >/= chlorpromazine (final drug conc. 10(-4) M); t1/2 (+/- SD) 21.