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PubMed1975

Flurbiprofen-sepharose chromatography of the prostaglandin synthetase from bovine seminal vesicles.

Flurbiprofen-Sepharose and Acetyl-Sepharose have been prepared by coupling dl-2-(2-fluoro-4-biphenylyl)propionic acid [Flurbiprofen] and acetic acid, respectively, to 3-(N-[3-aminopropyl)aminopropyl Sepharose 4B using a water soluble carbodiimide. The arachidonic acid oxygenase activity of solubilized bovine seminal vesicle microsomes is retarded during chromatography on Flurbiprofen-Sepharose but not Acetyl-Sepharose. Thus binding of the oxygenase to Flurbiprofen-Sepharose results from interaction with the immobilized inhibitor. However, the impure oxygenase is either not bound and/or not eluted in a biospecific manner since the abilities of flufenamic acid, R(+) and S(-)-5-cyclohexylindan-1-carboxylic acid, and R and S-Naproxen to remove the enzyme from Flurbiprofen-Sepharose do not parallel the relative efficacies of these compounds as prostaglandin synthesis inhibitors. Nevertheless, gradient elution of arachidonic acid oxygenase activity from Flurbiprofen-Sepharose with flufenamic acid provides a 15 fold enrichment of the enzyme from solubilized bovine seminal vesicle microsomes in 80% yield indicating that this chromatographic reagent can be a powerful tool for use in purification of the prostaglandin synthetase.

Animals↗
PubMed1992

Separation of non-steroidal anti-inflammatory agents using supercritical fluid chromatography.

Supercritical fluid chromatography (SFC) was investigated for the separation of non-steroidal anti-inflammatory agents (NSAIs). Three different stationary phases (SB-methyl-100, SB-biphenyl-30, and SB-cyanopropyl-50) were compared for the separation of the compounds. Baseline separation of a flufenamic acid, mefenamic acid, fenbufen and indomethacin mixture was achieved on the SB-biphenyl-30 column using a pressure gradient. A mixture containing flufenamic acid, mefenamic acid, acetylsalicylic acid, ketoprofen and fenbufen and another mixture containing ibuprofen, fenoprofen, naproxen, ketoprofen and tolmetin were well separated on the SB-cyanopropyl-50 column using pressure gradients. Typical analysis time for a mixture of NSAIs on the biphenyl or cyanopropyl column was approximately 20-25 min. Application of the method using the biphenyl column to the determination of NSAIs present in selected commercial dosage forms was demonstrated.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1976

Effect of anti-inflammatory drugs on lipase in vitro.

Mefenamic acid, and to a lesser extent, flufenamic acid have a significant inhibitory effect on lipolysis as determined by the action of mouse pancreas lipase on the dilauric (didodecanoic) acid ester of fluorescein. Ibuprofen, fenoprofen calcium, phenylbutazone, oxyphenbutazone and alclofenac had comparatively little effect.

Animals↗
PubMed2002

Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes.

The human ether-a-go-go related gene (HERG) product encodes for the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel that mediates repolarization of cardiac action potential. HERG channels are also potential targets of a large variety of pharmacological agents most of which tend to block HERG currents. In this study, we examined the effects of the non-steroidal anti-inflammatory agents, flufenamic acid and niflumic acid, on heterologously expressed HERG channels in oocytes. The cRNA of HERG (30 ng) was injected into Xenopus oocytes and currents were recorded using two-electrode voltage clamp technique in a low Cl(-) solution. Flufenamic and niflumic acids (10(-4)-5 x 10 (-4) M) enhanced the amplitude of outward currents evoked by depolarizing pulses. At potentials positive to 0 mV, an initial transient component was also evident in the presence of fenamates. Fenamates accelerated the activation rate of HERG channels and decelerated their deactivation. Flufenamic acid (5 x 10 (-4) M) shifted the I(tail)-V relationship from -26.7+/-0.1 to -31.4+/-0.2 mV. Neither flufenamic acid or niflumic acid affected the kinetics of HERG channel inactivation. Using a voltage protocol that mimicked the cardiac action potential, both fenamates increased the outward current during the plateau and during the phase 3 repolarization of action potential. The effects of the fenamates were blocked by the HERG channel blocker, E-4031 and were also not observed in water-injected oocytes. Our data suggest that fenamates enhance HERG currents and affect the action potential duration in the heart.

Action Potentials↗
PubMed1993

Inhibitors of nonselective cation channels in cells of the blood-brain barrier.

In the antiluminal membrane of isolated capillaries of rat and porcine brain (blood-brain barrier) nonselective cation channels with g = 31 pS were observed in cell-excised membrane patches. The channel inactivated by decreasing cytosolic Ca2+ below 1 microM and was inhibited by 1 mM ATP on the intracellular side. Anions and divalent cations did not pass the channel, but Na+ and K+ were equally permeant. Like the nonselective cation channel of rat exocrine pancreatic cells, the channel in cerebral capillary endothelial cells was inhibited reversibly by derivatives of diphenylamine-2-carboxylate (DPC), like 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC, ki = 1 microM), and flufenamic acid (ki = 4.9 microM). 4'-methyldiphenylamine-2-carboxylic acid (4-MDPC), 5-chloro-2(3-trifluormethylphenylamino)-3-nitrobenzoic acid, and 5-nitro-2-(3-phenylpropylamino)-2-carboxylic acid (NPPB), as well as the antiinflammatory drug ((Z)-5-chloro2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-ox o-1H-indole-1- carboxamide (Tenidap)) had a relatively low blocking potency (ki > 10 microM). Gadolinium (10 microM), a blocker of stretch-activated channels, inhibited the nonselective cation channel potently.

Adenosine Triphosphate↗
PubMed2005

Inhibition study of rabbit liver cytosolic reductases involved in daunorubicin toxication.

Anthracycline cardiotoxicity represents the most unfavorable side effect of these highly efficient anticancer drugs. Several biotransformation enzymes have been described to contribute to their cardiotoxicity. Besides the activities of CYP450 isoforms which lead to the generation of reactive oxygen species (ROS), the cytosolic reductases have attracted attention nowadays. The reductases known to metabolize anthracyclines to C13-hydroxyanthracyclines are carbonyl reductase (CR, 1.1.1.184) and the aldo-keto reductases (AKR1C2, 1.3.1.20; AKR1A1, 1.1.1.2). Their participation in the formation of the toxic C13-hydroxymetabolite has been investigated in rabbit using diagnostic inhibitors of CR and AKR1C2. The kinetics and the type of reductase inhibition exerted by the two inhibitors have been described and it was found that CR was the main daunorubicin reductase at both optimal and physiological pH with the kinetic parameters for daunorubicin reduction of Km = 17.01 +/- 1.98 microM and V(max) = 139.60 +/- 5.64 pcat/mg. The IC50 values for quercitrin and flufenamic acid were 5.45 +/- 1.37 microM and 3.68 +/- 1.58 microM, respectively. The inhibition was uncompetitive for both inhibitors and irreversible in the case of flufenamic acid.

Animals↗
PubMed1995

Small-conductance chloride channels in human peripheral T lymphocytes.

During whole-cell patch-clamp recording from normal (nontransformed) human T lymphocytes a chloride current spontaneously activated in > 98% of cells (n > 200) in the absence of applied osmotic or pressure gradients. However, some volume sensitivity was observed, as negative pressure pulses reduced the current. With iso-osmotic bath and pipette solutions the peak amplitude built up (time constant approximately 23 sec at room temperature), a variable-duration plateau phase followed, then the current ran down spontaneously (time constant approximately 280 sec). The anion permeability sequence, calculated from reversal potentials was I-, Br- > NO3-, Cl- > CH3SO3-, HCO3- > CH3COO- > F- > aspartate, gluconate, SO4(2-) and there was no measurable monovalent cation permeability. The Cl- current was independent of time during long voltage steps and there was no evidence of voltage-dependent gating; however, the current showed intrinsic outward rectification in symmetrical Cl- solutions. The conductance of the channels underlying the whole-cell current was calculated from fluctuation analysis, using power-spectral density and variance-vs.-mean analysis. Both methods yielded a single channel conductance of about 0.6 pS at -70 mV (close to the normal resting potential of T lymphocytes). The power spectral density function was best fit by the sum of two Lorentzian functions, with corner frequencies of 30 and 295 Hz, corresponding to mean open times of 0.54 and 5.13 msec. The pharmacological profile included rapid block by external application of flufenamic acid (50 microM), 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB, 100 microM), [6,7-dichloro-2-cyclopentyl-2,3- dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy] acetic acid (IAA-94, 250 microM) or 100 microM 1,9-dideoxyforskolin. The stilbene derivatives DIDS (4,4'-diisothiocyano-2,2' disulphonic acid stilbene, 500 microM) and SITS (4-acetamido-4'-isothiocyano-2,2'-disulphonic acid stilbene, 500 microM) prevented buildup of Cl- current after a 30-min preincubation at 500 microM. When tested in a mitogenic assay, DIDS, flufenamic acid, NPPB and IAA-94 all inhibited T-cell proliferation, suggesting a physiological function in addition to the observed volume sensitivity.

Biophysical Phenomena↗
PubMed1999

Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in HepG2 human hepatoblastoma cells.

The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigated in HepG2 human hepatoblastoma cells which do not express the estrogen receptor (ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular concentration of Ca2+. This effect was completely inhibited by the extracellular Ca2+ chelation with EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx pathways. This action of TAM was significantly inhibited by flufenamic acid (FA), a known non-selective cation channel blocker. Quantitative analysis of apoptosis by flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca2+ chelator, significantly inhibited TAM-induced apoptosis. These results suggest that intracellular Ca2+ signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells.

Apoptosis↗
PubMed1975

Effects of suprofen, an inhibitor of prostaglandin biosynthesis, on platelet function, plasma coagulation and fibrinolysis. I. In vitro experiments.

?The effects of suprofen, an inhibitor of prostaglandin biosynthesis, on human platelet function, fibrinolysis, proteolysis and coagulation in vitro were compared to those of reference compounds. Platelet aggregation induced by collagen, adrenaline and arachidonic acid was inhibited by suprofen depending on its concentration. Suprofen and indomethacin proved to have an equally inhibitory effect on platelet aggregation induced by collagen. Thrombin-induced aggregation was more inhibited by suprofen than by indomethacin. While the primary wave of A.D.P.-induced aggregation remained unchanged, the rate of disaggregation was enhanced by both compounds. Experiments on platelet factor-4 and 14C-serotonin release showed that suprofen and indomethacin reduced the platelet release reaction. Based upon results from experiments on synergism of suprofen with other compounds, on inhibition of arachidonic acid-induced platelet reactions and of prostaglandin E2-release, it is suggested that suprofen by inhibiting the prostaglandin biosynthesis in platelets also inhibits the platelet release reaction. In contrast to indomethacin and flufenamic acid, suprofen did not affect fibrinolysis or thrombin clotting activity. Tryptic proteolysis of albumin, however, was reduced by suprofen in a concentration-dependent and a substrate-competitive way. Tryptic decompisition of a synthetic substrate, on the other hand, was not reduced by either suprofen, indomethacin or flufenamic acid. These findings suggest that the observed reduction of albumin proteolysis by suprofen is related to an effect on the protein substrate rather than on the proteolytic enzyme itself.

Adenosine Diphosphate↗
PubMed1998

Effects of non-steroidal anti-inflammatory drugs on the luminol and lucigenin amplified chemiluminescence of human neutrophils.

A panel of non-steroidal anti-inflammatory drugs commonly used for therapeutic purposes was assessed for their effects on the respiratory burst of isolated human polymorphonuclear neutrophils. Cells were stimulated with opsonised yeast and the production of reactive oxygen species was measured by amplified chemiluminescence with luminol and lucigenin which are two luminogenic agents measuring different cellular events. A special attention was devoted to the establishment of dose-effect curves and calculation of ED50. Some of the drugs tested (acemetacine, diclofenac, flufenamic acid and niflumic acid) were able to decrease both luminol and lucigenin chemiluminescence in a dose-dependent manner reflecting an inhibitory effect on the respiratory burst. The most potent derivative was flufenamic acid (ED50 8 and 78 microM, respectively, with luminol and lucigenin), followed by diclofenac (21 and 98 microM), niflumic acid (97 and 227 microM) and acemetacine (585 and 427 microM). In contrast, several other drugs (flurbiprofen, ibuprofen, ketoprofen, piroxicam) stimulated both luminol and lucigenin chemiluminescence, suggesting a pro-oxidant activity. Acetylsalicylic acid (up to 1250 microM) was a modest inhibitor (maximum 25% inhibition) showing no dose-dependent effect and tolmetin (up to 125 microM) had no significant effect in both systems. The results were in agreement using both luminogenic agents, except for indomethacin, naproxen and tenoxicam which showed different kinds of effects. The unspecific and complex nature of the measurement systems used did not allow to give a complete mechanistic interpretation of the results, but the comparison with literature data gave some pertinent explanations for both anti- and pro-oxidant effects.

Acridines↗
PubMed1984

Differential effects of anti-inflammatory agents on lysosomal cysteine proteinases cathepsins B and H from rat spleen.

The reactivity and specificity of commonly used anti-inflammatory agents with lysosomal cysteine proteinases cathepsins B and H purified from rat spleen have been investigated. Of the different agents tested, flufenamic acid and indomethacin were known to be potent inhibitors of cathepsin B. A half-maximal inhibition of the activity of cathepsin B was achieved at drug concentrations of 7.6 X 10(-5) M of flufenamic acid and 4.0 X 10(-4) M of indomethacin. The inhibition by these two agents was of a non-competitive type with benzyloxy-carbonyl-phenylalanyl-arginine-4-methyl-7-coumarylamide (Z-Phe-Arg-MCA) as a substrate. The maximal inhibitory potencies of these agents for the cathepsin B activity were observed at pH 7.0. At pH values between 4.5 and 6.5, the inhibitory potencies were less than at pH 7.0. No preincubation time was needed for the reaction between these agents and cathepsin B. In contrast, cathepsin H was not affected by these two drugs even at the drug concentration of 10(-3) M at pH values between 4.5 and 8.0. Other anti-inflammatory agents including aspirin, sodium salicylate, phenylbutazone and prednisolone were found to be poorly or scarcely inhibitory for both cathepsins B and H.

Animals↗
PubMedDate not supplied

Mutagenicity examination of several non-steroidal anti-inflammatory drugs in bacterial systems.

The mutagenicity of 6 marketed non-steroidal anti-inflammatory drugs (aspirin, flufenamic acid, diclofenac sodium, indomethacin, naproxen and chloroquine) as well as 2 new anti-inflammatory drugs (tenoxicam and carprofen) was examined by using in vitro bacterial systems (repair test and reversion test). None of them was mutagenic on Ames' reversion test. However, they differed in their responses to repair tests. Tenoxicam, carprofen, aspirin, flufenamic acid and naproxen were not mutagenic in either rec- or pol-assays, whereas chloroquine only showed positive results in the pol-assay system. Indomethacin and diclofenac sodium exhibited a slightly stronger inhibitory activity against B. subtilis rec- mutant than against its rec+ counterpart in rec-assay, which was much weaker than AF-2. Thus their mutagenicity was questionable. These results confirm the usefulness of DNA-repair assays as a complementary endpoint to gene mutation in assessing the genotoxic potential of environmental compounds.

Anti-Inflammatory Agents↗
PubMedDate not supplied

A simple method for determining thiopental in plasma.

A simple rapid HPLC method for the measurement of thiopental is described. Plasma was deproteinised with 50% (v/v) acetonitrile in methanol containing flufenamic acid as an internal standard. Chromatography was carried out on a C-18 mu Bondapak reverse phase column using 220 mL of buffer (1.79 g of ammonium dihydrogen phosphate and 1.75 g of sodium sulfate adjusted to pH 7.9 with ammonium hydroxide) in 300 mL of methanol. Detection at 280 nm was near the absorption maxima of both thiopental and flufenamic acid. The method is linear up to 75 micrograms/mL and is therefore suitable for the measurement of thiopental in plasma from patients sedated by thiopental infusion. The sensitivity can be increased such that single dose studies can be investigated.

Chromatography, High Pressure Liquid↗
PubMed1984

Liquid-chromatographic determination of indomethacin in blood from newborns with patent ductus arteriosus.

This rapid, accurate "high-performance" liquid-chromatographic procedure is intended for measuring indomethacin in serum from neonates who are receiving indomethacin for symptomatic patent ductus arteriosus. Indomethacin and an internal standard (flufenamic acid) are extracted from serum or plasma with chloroform or diethyl ether at pH 5.0. For the chromatography we used a Waters' Radial Compression Separation System (Radial-NOVA PAK C18 reversed-phase column) and a mobile phase of methanol/sodium acetate buffer (10 mmol/L, pH 3.6), 70/30 by vol. The column effluent is monitored at 254 nm. Both indomethacin and flufenamic acid are eluted within 7 min. Indomethacin can be detected in concentrations as low as 50 micrograms/L, in 100-microL samples. Response varies linearly with indomethacin concentration to at least 2 mg/L. Analytical recovery is 75%; relative recovery is 100%. Precision is excellent. Using this method, we were able to improve the success rate for pharmacological management of symptomatic patent ductus arteriosus, especially in neonates with fast clearance rates for the drug.

Chromatography, High Pressure Liquid↗
PubMed1980

Decrease in peritoneal mast cell count in rats with adjuvant arthritis. II. Inhibition by anti-inflammatory and immunosuppressive drugs.

The following drugs were administered daily to adjuvant-injected rats: indomethacin, flufenamic acid, phenylbutazone, prednisolone, dexamethasone, methotrexate and 6-mercaptopurine. The effects on the decrease in the mast-cell count and histamine content of the peritoneal fluid were studied as well as the effect on the development of polyarthritis 14 days after adjuvant injection. At the doses tested, these drugs markedly inhibited changes in the parameters of peritoneal fluid. With the exception of flufenamic acid, the preventive effects on the decrease in the peritoneal mast-cell count paralleled the prevention of development of arthritic lesions. 6-Mercaptopurine administered daily for 5 consecutive days starting from day 0 was almost as effective as when it was given over the entire period (days 0 through 13). These results show that the decrease in the peritoneal mast-cell count is one of the symptoms of adjuvant disease in rats that can be used for the quantitative evaluation of antirheumatic drugs.

Animals↗
PubMed1996

Properties of K+ and Cl- channels and their involvement in proliferation of rat microglial cells.

Essentially pure (>95%) cultures of microglia were established from neopallia of newborn rats and used for whole-cell patch-clamp recording of electrophysiological properties and for proliferation studies. Two types of cultures were examined: 1) "Primary" cultures were grown in culture medium with serum and used within 3 weeks of isolation; 2) and "Colony-stimulating factor (CSF)-1-stimulated" cultures were derived from 3-week-old "primary" cultures by passaging and culturing them for several weeks longer in the presence of conditioned medium enriched in CSF-1. Microglia in the "primary" cultures expressed: 1) an inwardly rectifying K+ current (Kir) that was inhibited by Ba2+; 2) an outwardly rectifying K+ current (Kv) with many similarities to the cloned Kv1.3 channel of lymphocytes, including block by nanomolar concentrations of charybdotoxin (ChTX) and margatoxin (MgTX); and 3) an outwardly rectifying anion current with time- and voltage-independent gating. The anion current is activated reversibly under cell swelling conditions, i.e., after exposure to a hypo-osmotic bathing medium. The anion channels are highly permeable to Cl-, measurably permeable to gluconate (P(gluconate)/ PCl = 0.34), and blocked by flufenamic acid, 4-nitro-2-(3-phenylpropylamino)- benzoic acid (NPPB), and 6, 7-dichloro-2-cyclopentyl-2, 3-dihydro-2-methyl-1-oxo-1H-inden-5-yl (oxy) acetic acid (IAA-94). Microglia in the "CSF-1-stimulated" cultures expressed Kir and Cl- current, but not Kv current. Proliferation in the latter type of cultures could be slowed by omission of the CSF-1 enriched supernatant for 2 days and stimulated by adding back the conditioned medium. This "CSF-1-stimulated" proliferation was inhibited by Ba2+ (Kir blocker), and the Cl(-)-channel blockers flufenamic acid, NPPB, and IAA-94, whereas the Kv blockers ChTX and MgTX had no effect. Thus, Kir and Cl- channels appear to be necessary for "CSF-1-stimulated" proliferation of rat microglia, and there is no evidence that even a transient activation of Kv is necessary.

Animals↗
PubMed2004

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants.

Transthyretin (TTR) tetramer dissociation and misfolding affords a monomeric amyloidogenic intermediate that misassembles into aggregates including amyloid fibrils. Amyloidogenesis of wild-type (WT) TTR causes senile systemic amyloidosis (SSA), whereas fibril formation from one of the more than 80 TTR variants leads to familial amyloidosis, typically with earlier onset than SSA. Several nonsteroidal anti-inflammatory drugs (NSAIDs) stabilize the native tetramer, strongly inhibiting TTR amyloid fibril formation in vitro. Structure-based designed NSAID analogs are even more potent amyloid inhibitors. The effectiveness of several NSAIDs, including diclofenac, diflunisal, and flufenamic acid, as well as the diclofenac analog, 2-[(3,5-dichlorophenyl) amino] benzoic acid (inhibitor 1), has been demonstrated against WT TTR amyloidogenesis. Herein, the efficacy of these compounds at preventing acid-induced fibril formation and urea-induced tetramer dissociation of the most common disease-associated TTR variants (V30M, V122I, T60A, L58H, and I84S) was evaluated. Homotetramers of these variants were employed for the studies within, realizing that the tetramers in compound heterozygote patients are normally composed of a mixture of WT and variant subunits. The most common familial TTR variants were stabilized substantially by flufenamic acid and inhibitor 1, and to a lesser extent by diflunisal, against acid-mediated fibril formation and chaotrope denaturation, suggesting that this chemotherapeutic option is viable for patients with familial transthyretin amyloidosis.

Amyloidosis↗
PubMed2005

Novel properties of a mouse gamma-aminobutyric acid transporter (GAT4).

We expressed the mouse gamma-aminobutyric acid (GABA) transporter GAT4 (homologous to rat/ human GAT-3) in Xenopus laevis oocytes and examined its functional and pharmacological properties by using electrophysiological and tracer uptake methods. In the coupled mode of transport (Na+/ Cl-/GABA cotransport), there was tight coupling between charge flux and GABA flux across the plasma membrane (2 charges/GABA). Transport was highly temperature-dependent with a temperature coefficient (Q10) of 4.3. The GAT4 turnover rate (1.5 s(-l); -50 mV, 21 degrees C) and temperature dependence suggest physiological turnover rates of 15-20 s(-1). No uncoupled current was observed in the presence of Na+. In the absence of external Na+, GAT4 exhibited two distinct uncoupled currents. (i) A Cl- leak current (ICl(leak)) was observed when Na+ was replaced with choline or tetraethylammonium. The reversal potential of (ICl(leak)) followed the Cl- Nernst potential. (ii) A Li+ leak current (ILi(leak)) was observed when Na+ was replaced with Li+. Both leak currents were inhibited by Na+, and both were temperature-independent (Q10 approximately 1). The two leak modes appeared not to coexist, as Li+ inhibited (ICl(leak)). The results suggest the existence of cation- and anion-selective channel-like pathways in GAT4. Flufenamic acid inhibited GAT4 Na+/Cl-/GABA cotransport, ILi(leak), and ICl(leak), (Ki approximately 30 microM), and the voltage-induced presteady-state charge movements (Ki approximately 440 microM). Flufenamic acid exhibited little or no selectivity for GAT1, GAT2, or GAT3. Sodium and GABA concentration jicroumps revealed that slow Na+ binding to the transporter is followed by rapid GABA-induced translocation of the ligands across the plasma membrane. Thus, Na+ binding and associated conformational changes constitute the rate-limiting steps in the transport cycle.

Animals↗