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Biomedical subjects

A Balsamo

Publications and source records attributed to A Balsamo.

At least 55 records · Page 3Linked to original sources
PubMed1993

Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.

In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.

Animals↗
PubMed1992

Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.

The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.

Animals↗
PubMed1992

Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 patients defined as GH deficient.

Possible causes of error in the diagnosis of isolated GH deficiency are the variability of GH response to repeated tests, the existence of transient GH deficiencies, and the low GH levels found in short statured children with delayed puberty. Sixty-three patients with variously expressed GH deficiency were retested (1 sleep test and 2 pharmacological tests) after 1-3.9 yr of GH therapy (dose, 15 U/m2.week). Forty-eight subjects had arginine, L-dopa, and sleep tests (mean serum GH concentration) twice, while 15 had only arginine and L-dopa tests. All patients were retested 1 month after withdrawal from therapy. The criteria used to subdivide the patients were pubertal development and response to pharmacological and sleep tests at first diagnosis and on retesting. The initial diagnosis in 33 subjects (52.4%) was not confirmed, and 13 (20.6%) were no longer deficient on retesting. The percentage of normalization was high for the sleep test (43.9%), lower for the pharmacological test (24.5%), and lower still (12.9%) for pharmacological and sleep tests considered together. While none of the 28 subjects who remained prepubertal at retesting normalized in any of the tests, 13 of the 35 subjects retested during puberty did. When normalization was observed in pubertal subjects, it occurred predominantly in the sleep test. Growth velocity and height age/bone age increment ratio after the first year of therapy were no different for the groups of subjects classified according to GH secretion on retesting. Our study demonstrates that a number of children diagnosed as GH deficient do not have a true deficiency. However, such a diagnostic error seems to have little effect, at least in the first year of therapy, on the effectiveness of GH treatment.

Adolescent↗
PubMed1992

Hormonal profiles in Italian late-onset adrenal hyperplasia correlate with HLA class III polymorphisms.

To investigate the genetic polymorphisms of the HLA region in late-onset adrenal hyperplasia, 13 Italian patients affected by the disease were analyzed for: (1) HLA-A and -B typing; (2) restriction fragment length polymorphism (RFLP) of DR beta, DQ beta, DQ alpha, 21-hydroxylase A and B genes; (3) fourth complement fraction loci A and B (C4A and C4B), second complement fraction (C2) and properdin B factor (Bf) complement typing; (4) hormonal characteristics associated with some HLA haplotypes. HLA alleles B14 and DR beta 1 were found to be significantly more frequent in patients with respect to controls (relative risk: 8.7 and 7.2, p less than 0.001 and p less than 0.0001, respectively). Also C4B*2, 1 duplication was more frequent in patients than in normal subjects (23% vs. 1.5%, p less than 0.0001). Moreover, patients carrying a duplicated C4B (as well as those having the B14 antigen) showed higher 17-hydroxyprogesterone levels after ACTH stimulation. RFLP analysis of 21-hydroxylase genes with a specific probe revealed a duplication of 21-hydroxylase A gene in 40% of patients. All these individuals carried the C4A*2 B*2,1 phenotype and 75% of them displayed a clearly recognizable duplication at the C4B locus. These data support the hypothesis that in late-onset adrenal hyperplasia the 21-hydroxylase A pseudogene, even if inactive, may play a negative role in the regulation of 21-hydroxylase biosynthesis. Furthermore, we suggest analyzing class III phenotypes to screen the enzymatic defect.

17-alpha-Hydroxyprogesterone↗
PubMed1990

Long term growth hormone (GH)-releasing hormone and biosynthetic GH therapy in GH-deficient children: comparison of therapeutic effectiveness.

Twenty-five GH-deficient children were treated with GHRH (1-44), once daily sc for 6-24 months. At the 6th month of therapy, 40% of our patients showed a catch-up growth (responders), while the remaining 60% did not (nonresponders). No differences in auxological and biological variables at inclusion were found between the two groups. However, integrated GH secretion elicited by iv GHRH at inclusion was significantly (p less than 0.025) higher in responders than in non responders. During GHRH therapy, no significant increase in IGF 1/SmC was found in both groups. In all patients treatment was discontinued after 6-24 months, when its effect on growth rate failed. After a wash-out period of at least 6 months, patients were submitted to biosynthetic GH therapy. After 6 months of GH treatment a significant catch-up growth was found in both responder and non-responder children. Although the majority of GH-deficient children have hypothalamic rather than pituitary dysfunction, GHRH therapy is found to be less effective than GH treatment. Other methods of GHRH administration are worth investigating.

Adolescent↗
PubMed1990

Molecular design, synthesis, and antiinflammatory activity of a series of beta-aminoxypropionic acids.

Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.

Alanine↗
PubMed1990

Influence of growth hormone on thymic endocrine activity in humans.

The thymus produces humoral factors that induce the proliferation and differentiation of T cells which are responsible for cell-mediated immunity. Experimental data have suggested that this thymic hormone production is modulated by the neuroendocrine network and, in particular, by growth hormone (GH) and thyroid hormones. To study the role played by GH in thymic endocrine activity in humans, the circulating level of one of the best known thymic peptides, i.e. thymulin (Zn-FTS), has been determined, after a washout period of 2 weeks without GH treatment, in GH-deficient children before and after a single injection of GH. The basal thymulin level is consistently lower in GH-deficient children than in healthy age-matched controls. A single injection of GH induces a significant increment of the thymulin level for at least 48 h. Since thymulin activity may also depend on zinc bioavailability, on thyroid hormone turnover and on the eventual presence of thymulin-inhibitory substances, all these aspects have been checked. No supporting evidence regarding the existence of these kinds of interferences in GH-deficient children has been substantiated. A positive correlation has been found between the serum level of insulin-like growth factor I, but not of GH, and thymulin activity. These data suggest that GH may directly or indirectly modulate the thymic endocrine function in humans. Whether and to what extent such a modulation is relevant to the functioning of the immune system remains to be ascertained.

Adolescent↗
PubMed1990

Variability of growth hormone response to pharmacological and sleep tests performed twice in short children.

Forty-nine children with short stature (age range, 4.1-15.9 yr) were examined. Twenty-four (group 1) were submitted twice to an arginine and a sleep test (12-h overnight GH profile). Twenty-five patients (group 2) were submitted twice to an arginine and L-dopa test. Coefficients of variation were calculated between both the results of pharmacological (peak and area under the curve) and sleep tests [mean GH concentration (MGHC), peak, area under the curve, number of peaks above 5 micrograms/L, and peak area]. In group 1 the coefficient of variation of sleep test parameters was significantly lower than that of pharmacological tests (P less than 0.01 to less than 0.001). In the sleep test the area under the curve and MGHC were the most constant parameters. Group 2 showed no difference between the coefficients of variation of the two pharmacological tests. Considering groups 1 and 2 together, the coefficients of variation of the sleep test, in particular the MGHC and area under the curve, were lower than those of the two pharmacological tests. Eight of 24 subjects in group 1 showed a low GH level in 1 series of tests, and a normal level in the other series. Five of 18 subjects in group 2 showed an abnormally low GH response to the arginine and L-dopa tests and a normal response to the 2 repeated tests. Therefore, to prevent an erroneous interpretation of the GH test results, it is very important to perform a sleep test and repeat it whenever GH secretion seems to be deficient or at the lower limits of normalcy.

Adolescent↗
PubMed1990

Incidence of intratubular germ cell neoplasia in androgen insensitivity syndrome.

Gonadal histology was investigated by means of conventional microscopy in 6 patients with complete androgen insensitivity syndrome, in 11 with incomplete androgen insensitivity syndrome, and in 3 with 5 alpha-reductase syndrome. Twelve subjects were prepubertal and 8 pubertal. In all patients gonadal tissue was removed as a prophylactic measure and no patients gave rise to any clinical suspicion of a tumour. Eight patients with incomplete androgen insensitivity syndrome, 5 of whom (62.5%) were prepubertal, showed intratubular germ cell neoplasia and in 6 of them it was bilateral. Histochemical and immunohistochemical analysis showed considerable agreement between atypical morphological aspects and positive response to Schiff's periodic acid and to staining with the anti-placenta alkaline phosphatase antibody. Our patients were characterized by one of the highest reported incidences of intratubular germ cell neoplasia, particularly at prepubertal age. These findings would seem to indicate that a rethink is needed concerning the general opinion that patients with androgen intensivity syndrome have practically no risk of developing malignancy, and that orchidectomy is not advisable before puberty is completed.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Synthesis and antimicrobial properties of substituted 3-aminoxypropionyl and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams.

The substituted 3-aminoxyproprionyl (VII) and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams (VIII) which possess the monocyclic beta-lactam nucleus of aztreonam (IX) were synthesized by reaction of triethylammonium (3S, 4S)-3-amino-4-methyl-2-oxo-1-azetidinsulfonate with the aminoxy acids X and XI, respectively. Compounds VII and VIII were assayed in vitro for their antimicrobial properties against Gram-positive and Gram-negative bacteria, whether producers of beta-lactamases or otherwise. Both types of compounds (VII and VIII) exhibited a poor antibacterial activity towards Gram-positive bacteria, comparable to that of aztreonam. On the contrary VII and VIII proved to be practically inactive against Gram-negative microorganisms, towards which aztreonam exhibits a high degree of activity.

Anti-Bacterial Agents↗
PubMed1989

Synthesis and evaluation of the pharmacological activity of rigid analogues of sympathomimetic catecholamines derived from bicyclo[2.2.1]heptane.

endo-3-Amino-exo-2-(3,4-dihydroxyphenyl)-2-hydroxybicyclo[2.2.1]he ptane (4a) and its N-isopropyl derivative (4b) were synthesized and assayed for their adrenergic activity on various isolated preparations. Compounds 4a and 4b, tested up to a dose of 10(-4) M, did not reveal any activity, either stimulant or blocking, on the alpha- and beta-adrenoceptors. Possible rationalizations of the results obtained, however, are suggested.

Animals↗
PubMed1989

Synthesis and antimicrobial properties of substituted beta-aminoxypropionyl penicillins and cephalosporins.

Some beta-aminoxypropionyl penicillins (3) and cephalosporins (4 and 5), planned on the basis of the hypothesis that the (methyleneaminoxy)methyl group (greater than C = NOCH2) could be a "bioisoster" of either aryls or other aromatic groups, were synthesized and assayed for their antimicrobial properties. Compounds 3-5, tested on Gram-positive and Gram-negative bacteria, both sensitive to enzyme inactivation and otherwise, exhibited an activity trend that was not substantially different from that of the corresponding phenylacetamido derivatives taken as terms of comparison.

Ampicillin↗
PubMed1989

Effect of gonadectomy on growth hormone, IGF-I and sex steroids in children with complete and incomplete androgen insensitivity.

IGF-I, testosterone and estradiol levels were evaluated in 8 girls with androgen insensitivity immediately before and from 1 to 3 months after bilateral gonadectomy. In 6 patients GH secretion was evaluated before and after gonadectomy by means of an arginine test and in 3 a sleep test was also performed. Mean IGF-I level before surgery was significantly higher than that of normal controls (2850 +/- 1230 vs 1680 +/- 1040 U/l, p less than 0.025). After gonadectomy a significant decrease was evident for testosterone, estradiol and IGF-I levels. A positive correlation between IGF-I and estradiol levels was present before surgery (p less than 0.005). The presence of a correlation with estradiol, but not with testosterone, and the knowledge that this syndrome is due to an insensitivity to androgens, but not to estradiol, support the hypothesis that the estradiol level is the major determinant for the control of IGF-I values in these patients. After gonadectomy, a substantial decrease of the 12-h nocturnal GH secretion was evident. Comparison of the nocturnal GH levels before surgery of the 3 patients with those of normal subjects of the same age showed hormonal values higher than 1 SD over the mean values of control subjects. Even if the number of patients studied is too small to draw any definitive conclusion, these data may suggest that sex hormones play a role in the control of IGF-I levels, a function which seems to be mediated through GH secretion.

Adolescent↗
PubMed1988

Differential effects of 18- and 24-Gy cranial irradiation on growth rate and growth hormone release in children with prolonged survival after acute lymphocytic leukemia.

To evaluate the effects of two different doses of cranial irradiation on growth and growth hormone (GH) release, we studied 61 children with acute lymphocytic leukemia who had survived at least five years in continuous complete remission. Forty-three children received 24 Gy (group 1) and 18 children received 18 Gy (group 2). Height was evaluated at diagnosis, at the end of treatment, and 6, 12, and 24 months later. Growth hormone release was evaluated by arginine and levodopa tests after the end of treatment. After diagnosis, the height SD score decreased significantly in both groups; two years after the end of treatment, only group 1 showed an SD score for height that was still significantly lower than at diagnosis. Group 1 showed impaired GH responses to the tests and, compared with controls, group 1 in fact included a percentage of subjects with a normal response to levodopa (ie, greater than 8 micrograms/L) that was significantly lower (56.4% vs 83.3%) and a percentage of nonresponders to both tests that was significantly higher (21.6% vs 0%). These data indicate that only patients treated with lower cranial irradiation dosage (18 Gy) had complete growth recovery and normal GH responses to pharmacologic tests.

Arginine↗
PubMed1988

Haemorheologic and fibrinolytic evaluation in obese children and adolescents.

The haemorheologic condition was evaluated in 43 obese children and 35 controls. In 18 of the obese children and in 21 controls the euglobulin lysis time (ELT) was also studied. Blood viscosity at 94.5 and at 0.204 s-1 shear rates, plasma viscosity, fibrinogen and erythrocyte filtration time were significantly higher in obese than in control children. No significant differences were observed in haematocrit levels. Triglycerides, non-esterified fatty acids (NEFA), pre-beta-lipoprotein and insulin rates were all significantly higher in obese than in control children. There were no significant differences in glycaemia and in haemoglobin A1 values. ELT, both basal and after stimulation with 1-deamino-8-D-arginine-vasopressin (DDAVP), was significantly higher in the obese than in control children. The haemorheologic disturbances together with alterations of the haemostatic balance and fibrinolysis may be an important risk factor for the development of vascular changes at paediatric age.

Adolescent↗
PubMed1988

An anomalous effect of N-isopropyl substitution in determining beta-adrenergic activity.

We report unexpected results in an investigation of cyclic analogues of dopamine and norepinephrine possessing the structures 1-(aminomethyl)-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (3) and 1-(aminomethyl)-5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthalenol (7). N-Isopropyl substitution of these compounds, providing 4 and 8, brings about the total disappearance of their stimulant activity on beta-adrenergic receptors. On the basis of current knowledge about the structure-activity relationship of adrenergic drugs, it is difficult to provide an explanation for these results; however a tentative rationalization based on conformational considerations is suggested.

1-Propanol↗
PubMed1987

3-[(2-ethoxyphenoxy)methyl]piperidine derivatives. Synthesis and antidepressant activity.

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.

Animals↗