Polypharmacy for patients with chronic-degenerative diseases in a remote community, Puebla- México

Abstract Objective: To determine if patients with chronic degenerative diseases between 50-90 years of age have polypharmacy and drug interactions, at the Huajoyuca Health Center of Palacios, between June 2018-June 2019. Methodology: A descriptive, observational, non-experimental, statistical, retrospective, cross-sectional, unicentric research was carried out. The sample consisted of 56 files according to the inclusion criteria. Data were analyzed according to descriptive statistics and frequency histograms. Results: The mean age is 67.11 ± 9.6 years. There was a higher prevalence of polypharmacy in the 60-69 age range. Due to excessive medication consumption, women make up 82 percent of those affected. Patients with chronic-degenerative disorders are the most likely to have polypharmacy, and those with comorbid conditions even more, it was observed that the consumption and frequency of medications per patient is 4.08 ± 1.56 medications. The top drugs consumed daily are metformin (17.41%), hydrochlorothiazide (12.05%), B vitamin, acetylsalicylic acid glibenclamide with (11.16%), losartan (8.03%), enalapril (6.69%), captopril (4.91 %). 38 patients with (68%) had minor polypharmacy, 17 patients with (30%) had major polypharmacy, and 1 patient with (2%), had excess polypharmacy. Conclusion: In order from highest to lowest, patients with type 2 diabetes mellitus have minor polypharmacy, unlike hypertensive and dyslipidemic patients. The gender most affected by polypharmacy is the female with 82% vs. 18% the male gender of the population studied.

Homologous desensitization of human histamine H3 receptors expressed in CHO-K1 cells.

Histamine H3 receptors (H3Rs) modulate the function of the nervous system at the pre- and post-synaptic levels. In this work we aimed to determine whether, as other G protein-coupled receptors (GPCRs), H3Rs desensitize in response to agonist exposure. By using CHO-K1 cells stably transfected with the human H3R (hH3R) we show that functional responses (inhibition of forskolin-induced cAMP accumulation in intact cells and stimulation of [(35)S]-GTPγS binding to cell membranes) were markedly reduced after agonist exposure. For cAMP accumulation assays the effect was significant at 60 min with a maximum at 90 min. Agonist exposure resulted in decreased binding sites for the radioligand [(3)H]-N-methyl-histamine ([(3)H]-NMHA) to intact cells and modified the sub-cellular distribution of H3Rs, as detected by sucrose density gradients and [(3)H]-NMHA binding to cell membranes, suggesting receptor internalization. The reduction in the inhibition of forskolin-stimulated cAMP formation observed after agonist pre-incubation was prevented by incubation in hypertonic medium or in ice-cold medium. Agonist-induced loss in binding sites was also prevented by hypertonic medium or incubation at 4 °C, but not by filipin III, indicating clathrin-dependent endocytosis. Immunodetection showed that CHO-K1 cells express GPCR kinases (GRKs) 2/3, and both the GRK general inhibitor ZnCl2 and a small interfering RNA against GRK-2 reduced receptor desensitization. Taken together these results indicate that hH3Rs experience homologous desensitization upon prolonged exposure to agonists, and that this process involves the action of GRK-2 and internalization via clathrin-coated vesicles.

A single-point mutation (Ala280Val) in the third intracellular loop alters the signalling properties of the human histamine H3 receptor stably expressed in CHO-K1 cells.

BACKGROUND AND PURPOSE: An alanine to valine exchange at amino acid position 280 (A280V) in the third intracellular loop of the human histamine H3 receptor was first identified in a patient suffering from Shy-Drager syndrome and later reported as a risk factor for migraine. Here, we have compared the pharmacological and signalling properties of wild-type (hH3 R(WT)) and A280V mutant (hH3 R(A280V)) receptors stably expressed in CHO-K1 cells. EXPERIMENTAL APPROACH: The hH3 R(A280V) cDNA was created by overlapping extension PCR amplification. Receptor expression and affinity were assessed by radioligand (N-α-[methyl-³H]-histamine) binding to cell membranes, and receptor function by the inhibition of forskolin-induced cAMP accumulation and stimulation of ERK1/2 phosphorylation in intact cells, as well as stimulation of [³5S]-GTPγS binding to cell membranes. KEY RESULTS: Both receptors were expressed at similar levels with no significant differences in their affinities for H3 receptor ligands. Upon activation the hH3 RWT was significantly more efficacious to inhibit forskolin-induced cAMP accumulation and to stimulate [³5S]-GTPγS binding, with no difference in pEC50 estimates. The hH3 RWT was also more efficacious to stimulate ERK1/2 phosphorylation, but this difference was not significant. The inverse agonist ciproxifan was more efficacious at hH3 RWT to reduce [³5S]-GTPγS binding but, for both receptors, failed to enhance forskolin-induced cAMP accumulation. CONCLUSIONS AND IMPLICATIONS: The A280V mutation reduces the signalling efficacy of the human H3 receptor. This effect may be relevant to the pathophysiology of disorders associated with the mutation.

Histamine H3 receptors modulate depolarization-evoked [³H]-noradrenaline release from rat olfactory bulb slices.

We have studied the effect of histamine H(3) receptor (H(3)R) activation on the depolarization-evoked release of labeled neurotransmitters from slices of the rat olfactory bulb (rOB). The presence of pre-synaptic H(3)Rs was evidenced by the specific binding of the H(3)R ligand N-α-[methyl-(3)H]histamine to membranes from rOB synaptosomes (maximum binding, B(max), 106 ± 19 fmol/mg protein; dissociation constant, K(d), 0.68 ± 0.11 nM) which was inhibited by selective H(3)R ligands (immepip, (R)(-)-α-methylhistamine (RAMH) and clobenpropit) with affinities similar to those previously reported for H(3)Rs expressed in other rat brain areas. Perfusion of rOB slices with the selective H(3)R agonist RAMH (0.1 and 1 µM) had no effect on the release of [(3)H]-γ-aminobutyric acid ([(3)H]-GABA), [(3)H]-d-aspartate, [(3)H]-dopamine or [(3)H]-5-hydroxytryptamine ([(3)H]-5-HT) evoked by depolarization with high K(+) (20 or 40 mM). [(3)H]-Noradrenaline release induced by 20 mM K(+) was reduced in a modest but significant manner by RAMH (94.9 ± 1.7% and 83.1 ± 2.1% of control release at 0.1 and 1 µM, respectively). The effect of 1 µM RAMH was blocked by the selective H(3)R antagonist/inverse agonist clobenpropit (5 µM). When tested alone clobenpropit and a second H(3)R antagonist/inverse agonist, ciproxifan (both at 1 µM) significantly increased K(+)-evoked [(3)H]-noradrenaline release to 119.4 ± 4.2% and 120.0 ± 3.7% of K(+) alone, respectively. Ciproxifan (1 µM) had no effect on the depolarization-evoked release of the other labeled neurotransmitters. These data indicate that H(3)Rs with constitutive activity modulate noradrenaline release in rOB, presumably through a pre-synaptic action. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.