Homeopathic use of modern drugs: therapeutic application of the organism paradoxical reaction or rebound effect

When Samuel Hahnemann systematized homeopathy and the effects of drugs on the state of human health, he described the primary action of drugs and the following secondary and opposite reaction of the organism. Seeking to apply this secondary action or vital reaction of the organism as therapeutic method, he postulated the principle of similitude, i.e. the prescription to ill individuals of drugs that cause similar symptoms in the healthy (similia similibus curentur). In modern pharmacology, secondary action (vital reaction) of drugs is known as rebound effect or paradoxical reaction of the organism. It has been observed after discontinuation of several classes of palliative (enantiopathic) drugs, namely those that act according to the principle of contraries (contraria contrariis curentur). Although in this case it is associated with severe and fatal iatrogenic events, rebound effect might awaken a healing reaction when the very same drug is employed according to the principle of similitude. The validity of the principle of similitude is proved by scientific evidence on rebound effect, whereas conventional drugs primary (therapeutic, adverse and side) effects might be equated to pathogenetic manifestations and thus be homeopathically applied. For this purpose a homeopathic materia medica and repertory comprising 1,251 modern drugs was elaborated using the monographs described in The United States Pharmacopeia Dispensing Information as source (www.newhomeopathicmedicines.com). Thus, the therapeutic range of homeopathy is broadened through the addition of hundreds of new medicines that might be employed in every kind of disease including countless modern clinical syndromes.

Clostridium perfringens Beta2 toxin forms highly cation-selective channels in lipid bilayers

Clostridium perfringens is a potent producer of a variety of toxins. Well studied from these are five toxins (alpha, Beta (CPB), epsilon, iota and CPE) that are produced by seven toxinotype strains (A–G) of C. perfringens. Besides these toxins, C. perfringens produces also another toxin that causes necrotizing enterocolitis in piglets. This toxin termed consensus Beta2 toxin (cCPB2) has a molecular mass of 27,620 Da and shows only little homology to CPB and no one to the other toxins of C. perfringens. Its primary action on cells remained unknown to date. cCPB2 was heterogeneously expressed as fusion protein with GST in Escherichia coli and purified to homogeneity. Although cCPB2 does not exhibit the typical structure of beta-stranded pore-forming proteins and contains no indication for the presence of amphipathic alpha-helices we could demonstrate that cCPB2 is a pore-forming component with an extremely high activity in lipid bilayers. The channels have a single-channel conductance of about 700 pS in 1 M KCl and are highly cation-selective as judged from selectivity measurements in the presence of salt gradients. The high cation selectivity is caused by the presence of net negative charges in or near the channel that allowed an estimate of the channel size being about 1.4 nm wide. Our measurements suggest that the primary effect of cCPB2 is the formation of cation-selective channels followed by necrotic enteritis in humans and animals. We searched in databases for homologs of cCPB2 and constructed a cladogram representing the phylogenetic relationship to the next relatives of cCPB2.

Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera

On August 30, 2021, the WHO classified the SARS-CoV-2 Mu variant (B.1.621 lineage) as a new variant of interest. The WHO defines “comparative assessment of virus characteristics and public health risks” as primary action in response to the emergence of new SARS-CoV-2 variants. Here, we demonstrate that the Mu variant is highly resistant to sera from COVID-19 convalescents and BNT162b2-vaccinated individuals. Direct comparison of different SARS-CoV-2 spike proteins revealed that Mu spike is more resistant to serum-mediated neutralization than all other currently recognized variants of interest (VOI) and concern (VOC). This includes the Beta variant (B.1.351) that has been suggested to represent the most resistant variant to convalescent and vaccinated sera to date (e.g., Collier et al, Nature, 2021; Wang et al, Nature, 2021). Since breakthrough infection by newly emerging variants is a major concern during the current COVID-19 pandemic (Bergwerk et al., NEJM, 2021), we believe that our findings are of significant public health interest. Our results will help to better assess the risk posed by the Mu variant for vaccinated, previously infected and naïve populations.

Role of the 5-HT2A Receptor in Acute Effects of LSD on Empathy and Circulating Oxytocin

The psychedelic lysergic acid diethylamide (LSD) has experienced a revival in research, including clinical trials that evaluate LSD-assisted psychotherapy. LSD induces perceptual alterations and influences emotion processing in ways that may support psychotherapy. Here, we investigated the effects of LSD on emotional empathy and mediating role of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT2A receptor antagonist ketanserin (40 mg) using a placebo-controlled, double-blind, random-order, crossover design in 16 healthy subjects. The Multifaceted Empathy Test (MET) was used to assess the effects of LSD on emotional empathy. Plasma oxytocin levels were also measured. LSD dose-dependently increased implicit and explicit emotional empathy, with the highest 200 µg LSD dose having a significant effect compared with placebo. The 200 µg dose of LSD also moderately increased plasma oxytocin levels compared with placebo. Ketanserin reduced the LSD-induced elevations of oxytocin but not the LSD-induced increases in emotional empathy. These findings confirm that LSD enhances empathy, and this effect may be partially independent of its primary action on 5-HT2A receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT2A receptor stimulation, which is consistent with the psychedelic effect of LSD. Further studies are needed to investigate whether LSD may also enhance empathy and potentially produce therapeutic effects in patients who have deficits in empathy and impairments in social functioning.

Anti-inflammatory properties of the combination of meloxicam and N-acetyl-L-proline

The anti-inflammatory properties of the combination of meloxicam and atypical NSAID N-acetyl-L-proline (Groceprol®) after intragastric administration in a model of carrageenan paw edema in mice were studied. The average effective dose of N-acetyl-L-proline calculated by the regression analysis method in this model was 414 mg/kg, and the average effective dose of meloxicam was 2.85 mg/kg. In the combination in a ratio of 40:1, the activity of the compounds increases significantly, the ED50 of meloxicam decreases to 1 mg/kg, a similar value of N-acetyl-L-proline becomes 43 mg/kg. The same trend was also observed with another mass ratio of components of 20:1. The analysis of the pharmacodynamics of the combination of drugs according to the T. Chou method showed an additive type of interaction, typical for compounds with different mechanisms of primary action. It was established that a combination of N-acetyl-L-proline and meloxicam in the weight ratios of 40:1 and 20:1 demonstrate synergism, allowing to reduce the dose of the components in 2.7–9.6 times as compared with the effect of the drugs individually.The results of the study are the experimental justification for the use of anti-inflammatory synergistic combination of N-acetyl-L-proline and meloxicam.

The lysosomotrope GPN mobilises Ca2+from acidic organelles

ABSTRACTLysosomes are acidic Ca2+stores often mobilised in conjunction with endoplasmic reticulum (ER) Ca2+stores. Glycyl-L-phenylalanine 2-naphthylamide (GPN) is a widely used lysosomotropic agent that evokes cytosolic Ca2+signals in many cells. However, whether these signals are the result of a primary action on lysosomes is unclear in light of recent evidence showing that GPN mediates direct ER Ca2+release through changes in cytosolic pH. Here, we show that GPN evoked rapid increases in cytosolic pH but slower Ca2+signals. NH4Cl evoked comparable changes in pH but failed to affect Ca2+. The V-type ATPase inhibitor, bafilomycin A1, increased lysosomal pH over a period of hours. Acute treatment modestly affected lysosomal pH and potentiated Ca2+signals evoked by GPN. In contrast, chronic treatment led to more profound changes in luminal pH and selectively inhibited GPN action. GPN blocked Ca2+responses evoked by the novel nicotinic acid adenine dinucleotide phosphate-like agonist, TPC2-A1-N. Therefore, GPN-evoked Ca2+signals were better correlated with associated pH changes in the lysosome compared to the cytosol, and were coupled to lysosomal Ca2+release. We conclude that Ca2+signals evoked by GPN most likely derive from acidic organelles.

The Menstrual Cycle and the Dance Performance

The physiological alterations due to the variation in female hormones' concentrations, oestrogen and progesterone, will allow pregnancy or the period to occur. However, this hormone fluctuation across the menstrual cycle phases may affect way more than only the ability to get pregnant. Although the female hormones' primary action is related to the ovum's maturation and implantation, their variation causes many physiological and emotional secondary effects. It is expected that this interaction may, in turn, influence exercise performance, including dance performance; therefore, it is essential to understand better what happens in the body during the menstrual cycle. This understanding may allow better awareness and control of the symptoms, bringing a better quality of life and more remarkable dance performance.

Selenium-Ethylene Interplay in Postharvest Life of Cut Flowers

Selenium (Se) is considered a beneficial element in higher plants when provided at low concentrations. Recently, studies have unveiled the interactions between Se and ethylene metabolism throughout plant growth and development. However, despite the evidence that Se may provide longer shelf life in ethylene-sensitive flowers, its primary action on ethylene biosynthesis and cause-effect responses are still understated. In the present review, we discuss the likely action of Se on ethylene biosynthesis and its consequence on postharvest physiology of cut flowers. By combining Se chemical properties with a dissection of ethylene metabolism, we further highlighted both the potential use of Se solutions and their downstream responses. We believe that this report will provide the foundation for the hypothesis that Se plays a key role in the postharvest longevity of ethylene-sensitive flowers.

ОПІОЇДНІ РЕЦЕПТОРИ

The aim of our work was to study scientific information and to systematize data of domestic and foreign literature concerning the study of opioid receptors. The study of receptors localization and action is a promising and very complex task. Evidence of the complex effect of each group of receptors on the body is the fact that even those drugs that have a chemical structure in common with morphine, each have their own characteristics in the spectrum of action, side effects, the ability to pass the blood-brain barrier, efficacy and duration of anesthesia, addictive properties and other. This is eplained due to that the effect on receptors depends not only on the primary action of the drug, but also on the particular metabolism of a particular drug, since metabolites can be just the main factors influencing opioid receptors. In this context, it is important to note the huge number of factors that can change the duration and effectiveness of opioids, which involves a deep knowledge of this issue.Such differences partly explain th epecularity and characteristics of each opioid medication in terms of efficacy and duration of action, toxic inflance on the body, risk of complications and the occurrence of withdrawal effects, as well as particularities of use in patients with hepatic and renal impairment.

Ketamine and neuroticism: a double-hit hypothesis of internalizing disorders

Psychiatric disorders can often be viewed as extremes of personality traits. The primary action of drugs that ameliorate these disorders may, thus, be to alter the patient’s position on a relevant trait dimension. Here, we suggest that interactions between such trait dimensions may also be important for disorder. Internalizing disorders show important differences in terms of range of activity and speed of response of medications. Established antidepressant and anxiolytic medications are slow in onset and have differing effects across different internalizing disorders. In contrast, low-dose ketamine is rapidly effective and improves symptom ratings in all internalizing disorders. To account for this, we propose a “double hit” model for internalizing disorders: generation (and maintenance) require two distinct forms of neural dysfunction to coincide. One hit, sensitive to ketamine, is disorder-general: dysfunction of a neural system linked to high levels of the personality trait of neuroticism. The other hit is disorder-specific: dysfunction of one of a set of disorder-specific neural modules, each with its own particular pattern of sensitivity to conventional drugs. Our hypothesis applies only to internalizing disorders. So, we predict that ketamine will be effective in simple phobia and (perhaps partially) in anorexia nervosa, but would make no such prediction about other disorders where neuroticism might also be important secondarily (e.g. attention deficit hyperactivity disorder and schizophrenia).