PubMed Health⌕ Search

Biomedical subjects

R Hermann

Publications and source records attributed to R Hermann.

At least 55 records · Page 3Linked to original sources
PubMed2000

Pituitary and gonadal endocrine effects and pharmacokinetics of the novel luteinizing hormone-releasing hormone antagonist teverelix in healthy men--a first-dose-in-humans study.

UNLABELLED: BACKGROUND. Teverelix is a novel synthetic peptidic luteinizing hormone-releasing hormone (LHRH) antagonist. METHODS: Single subcutaneous morning doses of teverelix acetate (either 0.5, 1, 2, 3, or 5 mg base) were investigated in a randomized, single-blind, placebo-controlled, dose-escalating parallel-group design in healthy men. Six subjects received teverelix, and two subjects received placebo per dose level. Blood samples for lutropin, luteinizing hormone (LH), and follitropin, follicle-stimulating hormone (FSH), and testosterone, as well as for pharmacokinetics, were withdrawn up to 120 hours after dosing. Serum hormone levels were determined by electrochemicoluminescence immunoassays, and plasma teverelix concentrations were determined by radioimmunoassay. RESULTS: Teverelix led to a rapid, marked suppression of LH, testosterone and, to a lesser extent, FSH. Median maximum suppressions compared with predose levels were -93% for LH and -54% for FSH after teverelix 5 mg, and -93% for testosterone after teverelix 3 mg, respectively. After 5 mg teverelix, testosterone suppression <1 ng/mL started a median of 12 hours after dosing and lasted for a median of 33 hours. The duration of testosterone suppression increased with dose. Geometric means of peak teverilix plasma concentrations were 4.5 ng/mL (0.5 mg teverelix) to 49.0 ng/mL (5 mg teverelix) and tmax occurred between 1 and 4 hours after dosing. Geometric means of the area under the teverelix plasma concentration-time course from zero to time of the last quantifiable plasma concentration [AUC(O-tlast)] were 54.9 ng x h/mL (0.5 mg teverelix) to 881.8 ng x h/mL (5 mg teverelix). Median values for apparent terminal half-lives ranged from 24 to 75 hours. The most frequently reported adverse events were short-lasting mild injection-site reactions. CONCLUSIONS: Teverelix showed pronounced LH and testosterone suppressive effects after single subcutaneous doses in healthy men. Duration of hormone suppression increased with dose. Teverelix was well tolerated. This profile indicates potential for further clinical use.

Adult↗
PubMed2000

Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women.

PURPOSE: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. BACKGROUND: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established. METHODS: In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined. RESULTS: Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL. CONCLUSIONS: A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model.

Adult↗
PubMed2000

Methods for intense aeration, growth, storage, and replication of bacterial strains in microtiter plates.

Miniaturized growth systems for heterogeneous culture collections are not only attractive in reducing demands for incubation space and medium but also in making the parallel handling of large numbers of strains more practicable. We report here on the optimization of oxygen transfer rates in deep-well microtiter plates and the development of a replication system allowing the simultaneous and reproducible sampling of 96 frozen glycerol stock cultures while the remaining culture volume remains frozen. Oxygen transfer rates were derived from growth curves of Pseudomonas putida and from rates of oxygen disappearance due to the cobalt-catalyzed oxidation of sulfite. Maximum oxygen transfer rates (38 mmol liter(-1) h(-1), corresponding to a mass transfer coefficient of 188 h(-1)) were measured during orbital shaking at 300 rpm at a shaking diameter of 5 cm and a culture volume of 0.5 ml. A shaking diameter of 2.5 cm resulted in threefold-lower values. These high oxygen transfer rates allowed P. putida to reach a cell density of approximately 9 g (dry weight) liter(-1) during growth on a glucose mineral medium at culture volumes of up to 1 ml. The growth-and-replication system was evaluated for a culture collection consisting of aerobic strains, mainly from the genera Pseudomonas, Rhodococcus, and Alcaligenes, using mineral media and rich media. Cross-contamination and excessive evaporation during vigorous aeration were adequately prevented by the use of a sandwich cover of spongy silicone and cotton wool on top of the microtiter plates.

Bacteriological Techniques↗
PubMed2000

Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers.

Cetrorelix (CET), a potent luteinizing hormone-releasing hormone (LH-RH) antagonist, was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pickup and assisted reproductive techniques (ART), and is currently under clinical trials for benign prostate hyperplasia, endometriosis, and tumors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailability of 3 mg intravenously and subcutaneously administered CET in healthy male and female volunteers and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to link the plasma concentrations of CET to the T and LH suppression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were measured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, respectively. Pharmacokinetics of CET was explained by a three-compartment model for the IV route and by a two-compartment model with first-order absorption for the SC route. Average absolute bioavailability after SC administration was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single IV and SC doses of CET caused immediate and distinct suppression of LH, FSH, and T levels by 80%, 45% and 95% of their baseline levels, respectively. The duration of hormone suppression was longer for the SC route. An indirect-response PK-PD Emax model was developed to link the measured CET plasma concentrations with the respective T or LH levels. In addition, the circadian rhythm of T levels was accounted by including a cosine function in a second separate PD model. The PD model with cosine function was applied to T baseline levels as well as to the suppressed concentrations after CET dosing. The two models adequately described the PK-PD relationship between plasma levels of CET and T suppression following IV and SC dosing. The EC50 values (mean +/- SD) for the suppression of T were similar (p > 0.05) between the two routes of administration and the two models.

Adult↗
PubMed2000

Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6.

OBJECTIVES: The factors determining the pathogenesis of transient and permanent neonatal diabetes mellitus are poorly characterized. The purpose of this study was to examine the role of chromosome 6 in the pathogenesis of neonatal diabetes mellitus and to detect differences between these 2 phenotypes. METHODS: Microsatellite markers (D6S334, D6S286, D6S310, D6S308, D6S292, D6S311, and D6S403) and human leukocyte antigen DQ alleles were examined using polymerase chain reaction and DNA fragment electrophoresis in 3 patients with transient and 3 patients with permanent neonatal diabetes mellitus. Humoral markers of islet cell autoimmunity and clinical characteristics were analyzed in the 2 groups. RESULTS: A patient with transient neonatal diabetes mellitus (TND) and macroglossia carrying paternal uniparental isodisomy (UPD) of chromosome 6 has been identified. The isodisomy affected the whole chromosome; no maternal chromosome 6 sequences were detected. The permanent neonatal diabetes mellitus cases and the other 2 cases with TND did not have UPD. None of the patients had high-risk type 1 diabetes human leukocyte antigen DQ alleles and most infants were negative for islet cell-specific autoantibodies indicating that none of the 2 forms of neonatal diabetes mellitus is likely to be of autoimmune origin. An association of TND and persistent granulocytopenia is described for the first time. CONCLUSIONS: We propose that transient and permanent forms of neonatal diabetes mellitus have different genetic background and represent different disease entities. TND is associated with UPD of chromosome 6 suggesting that an imprinted gene on chromosome 6 is responsible for this phenotype. It seems that 2 copies of the paternal allele are necessary for the development of TND; therefore, it is likely that overexpression of a putative gene located on chromosome 6 alters pancreatic beta-cell maturation and insulin secretion.

Chromosomes, Human, Pair 6↗
PubMed2000

On the photochromism of spiro

The recently synthesized spiro[cyclohexadiene-dihydroacridines] consisting of perpendicularly arranged aroylcyclohexadiene and N-methyl-dihydroacridine moieties were found to have photochromic properties. The reversible photoisomerization from the spiro compound toward a colored merocyanine caused by C-C bond cleavage in the cyclohexadiene was studied by stationary and time-resolved measurements of their optical spectra. The course of the absorption under UV and visible irradiation, respectively, and HPLC analysis of the photoproducts result in the determination of excitation energy-dependent quantum yields for the merocyanine formation and, in reverse, the ring closure, as well as degradation. Whereas the thermal back reaction completely recovers the spiro compound (k approximately 6.8 x 10(-4) s-1, T = 22 degrees C), degradation of the merocyanine under irradiation at 480 nm has a probability of about 6%. Picosecond-resolved measurements of the fluorescence and the transient absorption show that photoisomerization occurs via the first excited singlet state within 100 ps depending on the activation barrier.

Journal Article↗
PubMed1999

Characterization of glycosylphosphatidylinositol-linked molecule CD55/decay-accelerating factor as the receptor for antibody SC-1-induced apoptosis.

The human monoclonal antibody SC-1 induces apoptosis of stomach carcinoma cells and is currently used in a clinical Phase II trial. The antibody binds to a target molecule that is preferentially expressed on diffuse- and intestinal-type stomach cancer cells and shows a very restricted expression on other normal and malignant tissues. In this paper, we show that the SC-1 receptor is a stomach carcinoma-associated isoform of CD55 [membrane-bound decay-accelerating factor (DAF)-B] with a relative molecular mass of approximately 82 kDa. The antigenic site of SC-1 is an N-linked carbohydrate residue. Cross-linking of the DAF receptor increases apoptotic activity. SC-1 binding induces tyrosine phosphorylation of three proteins of approximately 60, 75, and 110 kDa, whereas a serine residue of an approximately 35-kDa protein is dephosphorylated. Expression of caspase-3 (CPP32) and caspase-8 (FLICE) is elevated, and activation of these caspases occurs. These data show that a tumor-specific variant form DAF is involved in apoptosis and can be used for adjuvant therapeutical purposes on gastric carcinoma.

Antibodies, Monoclonal↗
PubMed1999

Mitogenic autoantibodies in Helicobacter pylori-associated stomach cancerogenesis.

Colonization of the bacterium Helicobacter pylori of gastric mucosa plays an important role in stomach carcinogenesis, while the gastric mucosa and nearby lymphoid tissue are active sites of humoral immunity against both bacteria and tumor. In a broad study on the humoral immunity of stomach-cancer patients (5 patients with diffuse- and intestinal-type stomach carcinoma), we immortalized spleen cells by using human hybridoma technology and isolated 11 hybrid clones (9 IgM, 1 IgG and 1 IgA) which react with defined proteins on different stomach-cancer cells and, interestingly, also with distinct proteins on H. pylori; 4 of these antibodies are mitogenic and stimulate the proliferation of stomach-cancer cells in vitro. Furthermore, immunohistochemical studies define these 4 clearly as autoantibodies, in view of their reactivity to normal epithelial cells. Sequence analysis of the genes for the immunoglobulin heavy (V(H)) and light (V(L)) chain variable regions revealed that most of the human antibodies belong to the V(H)3, Vlambda I and III gene families (DP-49, DPL-5 and DPL-23) and are germ-line configured.

Autoantibodies↗
PubMed1999

Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.

Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.

Administration, Oral↗
PubMed1999

Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data.

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.

Adult↗
PubMed1999

Lack of interaction between thioctic acid, glibenclamide and acarbose.

AIMS: Thioctic acid (TA), glibenclamide and acarbose are widely used to either alone or concomitantly treat patients suffering from noninsulin-dependent diabetes (NIDDM). This study systematically investigated drug-drug interactions between TA and glibenclamide and TA and acarbose. METHODS: Fourteen male and 10 female healthy volunteers participated a randomized, open three period cross over trial (treatments A-C) followed by a fourth period (treatment D). A baseline profile for plasma insulin and glucose concentrations, variables which served as pharmacodynamic measures, was assessed before entering the trial. Treatments were A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)-TA and S(-)-TA as well as glibenclamide concentrations were measured with specific analytical methods. RESULTS: There was no clinically relevant change of TA enantiomer pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma insulin and glucose concentrations did not indicate an interaction between TA and glibenclamide or TA and acarbose. Glibenclamide had the expected effect on insulin and glucose levels independent of comedication. There were only minor and short lasting adverse events with the majority being (expected) hypoglycaemic symptoms occurring during the treatments with glibenclamide. CONCLUSIONS: Coadministration of single doses of TA and glibenclamide or TA and acarbose does not appear to cause drug-drug interactions.

Acarbose↗
PubMed1999

Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.

Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake.

Adenocarcinoma, Mucinous↗
PubMed1999

Ultrastructural localization of proteins involved in sea urchin biomineralization.

Three skeletal tissues of the adult echinoid Paracentrotus lividus (the pedicellaria primordium, the test, and the tooth) were immunolabeled with three sera raised against the total mineralization organic matrix and two specific matrix proteins (SM30 and SM50) from the embryo of the echinoid Strongylocentrotus purpuratus. Two conventional chemical fixation protocols and two high-pressure freezing/freeze-substitution protocols were tested. One conventional protocol is recommended for its good preservation of the ultrastructure, and one high-pressure freezing/freeze-substitution protocol is recommended for its good retention of antigenicity. Immunolabeling was obtained in the three adult tissues. It was confined to the active skeleton-forming cells and to the structured organic matrix. The results indicate that the matrix proteins follow the classical routes of secretory protein assembly and export and suggest that SM30 and SM50 are a part of the tridimensional network formed by the organic matrix before the onset of mineralization. They show that the genetic program of part of skeletogenesis is conserved among different calcification models and developmental stages.

Animals↗
PubMed1999

[Mutational pattern of Ig-VH genes of synovial B-lymphocytes from different anatomical locations in a rheumatoid arthritis patient].

Synovial B-lymphocytes which are a constant feature of RA synovialitis are expanded in an antigen dependent manner. To understand the nature of the antigen driving the B-cell expansion it would be interesting to know whether there exists a restricted number of antigens. Therefore the usage of germline genes and the mutational pattern of Ig-VH-genes from synovial B-cells from 3 different anatomical regions with different onsets of local disease were analysed. Together with an immunohistological study characterising the inflammatory infiltrate (CD3, CD22, CD23 and Ki-M4), RNA was prepared from tissue sections taken from the right and left peroneal tendons and right elbow of a patient with seropositive RA. The corresponding cDNA was amplified using specific VH primers and the obtained variable region sequences were compared to their closest germline counterparts on the EMBL/Genbank data base. The molecular analysis demonstrated somatically mutated VH genes (total R/S ratios in CDR 1 + 2: right peroneal tendon 7.5; left peroneal tendon 3.5 and right elbow 3.0) in all three different regions, with two clones presenting aminoacid deletions. The values of total R/S ratios correlated directly to the duration of local disease. The aminoacid sequences from the different locations exhibited strong homology among each other. This homology was of 77% for the 19 clones belonging to the VH1 family. Immunohistochemistry demonstrated in two locations a dense follicle-like infiltrate with FDC-network, the third location presented a non-follicular distribution of lymphozytes without FDC. Hence the R/S values were correlated directly with the duration of local disease, it appears that here is an ongoing antigen-dependent B-cell activation in joints probably occurring in the FDC-networks. Moreover this study suggests--due to a high homology among the VH aminoacid sequences from B-cells of different anatomical regions--that a restricted number of antigens is involved in the B-cell expansion of RA patients.

Amino Acid Sequence↗
PubMed1998

[Chronic hepatitis C--therapeutic modalities for interferon failure].

Treatment with alpha-interferon-monotherapy for chronic hepatitis C is rather unsatisfactory. After a 6-12-months course of interferon three times 3 MU weekly, only a minority of 10-25% of interferon-naive patients have a sustained response with normalisation of ALT and elimination of viremia. The majority of patients does not respond or relapses shortly after treatment. In these patients an individual risk factor profile should be worked out based on evaluation of known factors predictive for response which may aid in the therapeutic decision concerning indication and type of a second line treatment. This review on current therapeutic options for second line treatment focuses on interferon-retreatment and combination therapy with ribavirin and amantadine.

Amantadine↗
PubMed1998

Immuno-cross-reactivity of CUT-1 and cuticlin epitopes between ascaris lumbricoides, Caenorhabditis elegans, and Heterorhabditis.

Cuticlin is the insoluble residue of nematode cuticle. It has been proved that cuticlin and CUT-1-like epitopes are conserved between the free-living Caenorhabditis elegans and the entomopathogenic nematode Heterorhabditis sp. The cloning of a cut-1 homologous gene from the animal intestinal parasite Ascaris lumbricoides has allowed us to extend the study of immuno-cross-reactivity at the ultrastructural level to this important species. Antibodies against recombinant CUT-1 protein and against cuticlin from Ascaris as well as from C. elegans were used for immuno-labeling ultrathin sections of high-pressure cryoprocessed worms. All the antisera used showed the same specific pattern of localization on sections of C. elegans of Heterorhabditis dauer larvae, and of Ascaris larvae in mature eggs. It was also shown that sera raised against the cuticlin residue contain anti-CUT-1 antibodies. CUT-1-like proteins are thus possibly important components in the immune response of hosts to invading nematodes. The results presented support the use of C. elegans as a model for the study of vertebrate parasitic nematodes.

Animals↗
PubMed1998

The A mating type and blue light regulate all known differentiation processes in the basidiomycete Coprinus cinereus.

Monokaryons of Coprinus cinereus constitutively form small spores (oidia) in the aerial mycelium. Some strains also produce large, inflated single cells (chlamydospores) at the agar/air interface, and hyphal aggregates (hyphal knots) that can develop into sclerotia. Monokaryons show various reactions upon transformation with heterologous A mating type genes. Production of oidia in such A-activated transformants is repressed in the dark and induced by blue light. Five of six monokaryons tested following transformation with A genes showed induced production of hyphal knots and sclerotia in the dark, and at least three strains showed enhanced chlamydospore production in the dark. Continuous incubation under blue light inhibited formation of hyphal knots, sclerotia and chlamydospores in both competent monokaryons and in A-activated transformants. On artificial medium and on a 12 h light/12 h dark regime, A-activated transformants of one distinct monokaryon (218) formed fruit-body primordia that were arrested in development before karyogamy. Our studies show that A mating type genes control all major differentiation processes in Coprinus, but whether developmental processes can proceed depends on the genetic background of the strain.

Cell Differentiation↗