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PubMed1998

Pharmacologic pain management in children: a review of intervention research.

In the past decade, an explosion of interest in pediatric pain has resulted in the proliferation of research studies. This review examines 41 studies that focus on pharmacologic interventions in children during the last decade. Criteria for inclusion in this paper were studies that (1) tested a pharmacological intervention prospectively, (2) were conducted with children only, (3) had a sample size over 30, (4) randomly assigned participants to two or more groups, and (5) provided sufficient methodological and statistical detail for critique. Studies focused on postoperative and procedural pain, were conducted most frequently with pre-school-aged children or older, and demonstrated the efficacy of pharmacologic interventions.

Adolescent↗

PubMed2003

Managing gastroesophageal reflux disease: from pharmacology to the clinical arena.

GERD is a condition affecting patients throughout the 24-hour period, although the nighttime interval may require special consideration because of the pharmacologic profile of the agents used to treat GERD, and the normal physiologic processes rendering nighttime GERD particularly damaging. GERD patients should be managed with appropriate therapy proportional to the frequency and severity of their symptoms. PPIs are the most potent inhibitors of acid secretion, and with a thorough knowledge of their pharmacologic properties, clinicians can be helped in identifying strategies that can maximize the benefits of their potency (see Table 2). PPIs offer significant benefit to persons requiring longer-term therapy because they are potent agents and offer ease of dosing and favorable drug interaction and adverse effect profiles. However, it is necessary that clinicians understand the physiology and pharmacology of acid secretion to use them appropriately. Inevitably, proper therapeutic treatment demands that variables such as pharmacokinetics, ethnicity (metabolic profile), and the normal physiology of acid secretion be considered when choosing an appropriate PPI.

Anti-Ulcer Agents↗

PubMed2003

A topological-substructural molecular design (TOPS-MODE) approach to determining pharmacokinetics and pharmacological properties of 6-fluoroquinolone derivatives.

The topological-substructural molecular design approach was used to estimate the human bioavailability (F) and the minimum inhibitory concentration (MIC90) against Streptococcus pneumoniae from a data set of 17 and 19 fluoroquinolone derivatives, respectively. Both pharmacokinetics and pharmacological properties were well described by the present approach. The total spectral moments and local spectral moments that include the different fluoroquinolone rings, polar and non-polar areas and their interactions were calculated and weighted with the standard dipole moments and the electronegative difference between the atoms that form a bond. In order to obtain a qualitative model that permits the classification of drugs with high and moderate bioavailability, a linear discriminant analysis was carried out. The percentage of correct classification was 100% for compounds of the training set. The leave-one-out cross validation procedure showed an 88.23% of correct classification. Also, a quantitative model, by the piecewise linear regression was developed. The theoretically predicted values for human bioavailability was assessed by a correlation with in vivo rat bioavailability and the regression equation was used to predict this biopharmaceutical property for two new pre-clinical 6-fluoroquinolone derivatives. On the other hand, a linear regression model that explained the 84% of variance was developed to predict the MIC90 values. Finally, the role of a pharmacokinetic and pharmacological relationship in the design of new fluoroquinolones was evaluated in the Sitafloxacin framework, where 13 substituents were analyzed; halogens and methoxy groups had the best contributions to both properties. The present approach proved to be a good method for studying the pharmacokinetics and the pharmacological properties of new 6-fluoroquinolone candidates in drug development studies.

Animals↗

PubMed2000

Pharmacological activities of Vitex agnus-castus extracts in vitro.

The pharmacological effects of ethanolic Vitex agnus-castus fruit-extracts (especially Ze 440) and various extract fractions of different polarities were evaluated both by radioligand binding studies and by superfusion experiments. A relative potent binding inhibition was observed for dopamine D2 and opioid (micro and kappa subtype) receptors with IC50 values of the native extract between 20 and 70 mg/mL. Binding, neither to the histamine H1, benzodiazepine and OFQ receptor, nor to the binding-site of the serotonin (5-HT) transporter, was significantly inhibited. The lipophilic fractions contained the diterpenes rotun-difuran and 6beta,7beta-diacetoxy-13-hydroxy-labda-8,14-dien . They exhibited inhibitory actions on dopamine D2 receptor binding. While binding inhibition to mu and kappa opioid receptors was most pronounced in lipophilic fractions, binding to delta opioid receptors was inhibited mainly by a aqueous fraction. Standardised Ze 440 extracts of different batches were of constant pharmacological quality according to their potential to inhibit the binding to D2 receptors. In superfusion experiments, the aqueous fraction of a methanolic extract inhibited the release of acetylcholine in a concentration-dependent manner. In addition, the potent D2 receptor antagonist spiperone antagonised the effect of the extract suggesting a dopaminergic action mediated by D2 receptor activation. Our results indicate a dopaminergic effect of Vitex agnus-castus extracts and suggest additional pharmacological actions via opioid receptors.

Animals↗

PubMed2001

Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors.

The clinical development of aromatase inhibitors (AIs) has been closely guided by clinical pharmacological investigations. During the early phases of development studies were focused on dose-related pharmacological effectiveness and specificity. More recently attention has been given to the metabolic changes which AIs elicit, with particular regard to their potential use in early breast cancer and the prophylactic setting. Pharmacological effectiveness has been studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not helpful in comparing the third generation inhibitors: anastrozole, letrozole, exemestane. All three of these compounds suppress whole body aromatisation by >96%. Most recently, we have established that significantly greater inhibition is achieved by letrozole than anastrozole at their clinically used dosages. This more complete inhibition is paralleled by significantly greater suppression of E1S.A broad panel of endocrine investigations has indicated that these compounds have essentially complete specificity at their clinical dosages. A minor androgenic effect of exemestane is revealed by a significant suppression of sex hormone binding globulin (SHBG). Lipid and bone biomarker data are being collected in many current studies. A pharmacokinetic interaction has been established between letrozole and tamoxifen, whereby reduced circulating levels of letrozole are found with combined application. Neither anastrozole nor letrozole have any effect on plasma concentrations of tamoxifen when given in combination with it.

Aromatase Inhibitors↗

PubMedDate not supplied

Pharmacological characterization of dopamine receptors in the corpus allatum of Manduca sexta larvae.

Dopamine receptors previously identified in corpora allata (CA) of Manduca sexta last instars on the basis of dopamine effects on JH (juvenile hormone)/JH acid biosynthesis and cyclic AMP (cAMP) accumulation, were characterized pharmacologically. For this study, a broad spectrum of agonists or antagonists of D1, D2, D3 or D4 dopamine receptors, together with the dopamine metabolite N-acetyl-dopamine, other neurotransmitters and their agonists/antagonists, were tested for their effects on gland activity and cAMP production. The lack of effect of other neurotransmitters supports the specificity of the effect of dopamine and the dopamine specificity of the receptors. Only the D2 receptor antagonist spiperone had a potent effect on JH biosynthesis and cAMP formation by CA taken on day 0 of the last stadium, when dopamine stimulates both activities and thus appears to be acting via a D1-like receptor. Several other D2 receptor antagonists, and D1, D2/D1 and D4,3/D2 receptor antagonists were less effective. Thus, the D1-like receptor of the Manduca CA appears to be distinct pharmacologically from vertebrate D1 receptors. By contrast, a number of D2 agonists/antagonists had a significant effect on JH acid biosynthesis and cAMP production by the CA from day 6 of the last stadium, when dopamine inhibits both activities and thus appears to be acting via a D2-like receptor. Certain D1-specific agonists/antagonists were equally effective. The Manduca D2-like receptor therefore bears some pharmacological resemblance to vertebrate D2 receptors. N-acetyl dopamine acted as a dopamine agonist with day 6 CA, the first identified function for an N-acetylated biogenic amine in insects. Dopamine was found to have the same differential affect on the formation of cAMP in homogenates of day 0 and day 6 brains as it did with CA, and in the same concentration range. Dopamine receptor agonists/antagonists affecting cAMP formation by day 0 and day 6 CA homogenates had similar effects with brain homogenates. By contrast, dopamine only stimulated cAMP formation by homogenates of day 0 and day 6 abdominal or ventral nerve cord. These results suggest that D1- and D2-like dopamine receptors of Manduca are regionally as well as temporally localized.

Animals↗

PubMed2002

Atrial fibrillation after coronary bypass: etiology and pharmacologic prevention.

Coronary bypass surgery is performed on over 400,000 patients each year in the United States. Atrial Fibrillation (AF) is the most common complication after bypass surgery. The significance of its occurrence lies not only in the potentially dangerous and physiologic derangement to patients, but also in the impact it has on the utilization of health care resources. Several clinical observations suggest that the occurrence of atrial fibrillation after bypass surgery has some unique features related to the perioperative circumstances. Numerous therapies, both pharmacologic and non-pharmacologic have been tested to prevent this tenacious problem. Its persistence continues to intrigue cardio-thoracic surgeons, cardiologists, anesthesiologists and the insurers alike. In this review we discuss the published literature on postbypass AF, with a special emphasis on pharmacologic prevention.

Adrenergic beta-Antagonists↗

PubMed2002

Syntheses and pharmacological evaluation of two potent antagonists for dopamine D4 receptors: [11C]YM-50001 and N-[2-[4-(4-Chlorophenyl)-piperizin-1-yl]ethyl]-3-[11C]methoxybenzamide.

Two benzamide derivatives as dopamine D4 receptor antagonists, YM-50001(4) and N- [2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide (9), were labeled by positron-emitter (11C), and their pharmacological specificities to dopamine D4 receptors were examined by quantitative autoradiography and positron emission tomography (PET). Radiosyntheses were accomplished by O-methylation of corresponding phenol precursors (5 and 10) with [11C]CH3I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [11C]4 showed the highest binding in the striatum, which was inhibited not only by 10 microM 4 but also by 10 microM raclopride, a selective dopamine D2 receptor antagonist. In contrast, [11C]9 showed the highest binding in the cerebral cortex, which was inhibited by several D4 receptor antagonists (9, RBI-254, L-745,870), but not by any other receptor ligands (D1/D5, D2/D3, 5-HT1A, 5-HT2A, sigma1 and alpha1) tested. In vivo brain distribution of [11C]9 in rat showed the highest uptake in the frontal cortex, a region that has a high density of D4 receptors. These results indicate that the pharmacological property of [11C]9 matches the rat brain D4 receptors, but that of [11C]4 rather appears to match the rat brain D2 receptors. The results for the benzamide [11C]9 prompted us to further evaluate its potential as a PET radioligand for D4 receptors by employing PET on monkey brain. Unfortunately, in contrast to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous 11C]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only faintly expressed in the brain, 11C]9 with an extremely high specific activity (1810 GBq/micromol) was used for PET study. However, the effort to determine the specific binding for D4 failed. These results indicate that both of the benzamide derivatives would not be suitable radioligands for D4 receptors with PET.

Animals↗

PubMed2003

Gender differences in limbic responsiveness, by SPECT, following a pharmacologic challenge in healthy subjects.

Limbic system functioning is integral to the control and modulation of affect, motivation, reward, and memory. Neuropsychiatric disturbances involving disruptions in these cognitive and emotional dimensions exhibit different prevalence rates for men and women. Gender-specific differences in this integrated brain area may therefore be important in understanding both normal behavioral functioning and the etiologic underpinnings of neuropsychiatric disorders. To further explore such differences in limbic system function, we assessed regional cerebral blood flow, by SPECT, in men and women following the administration of procaine. Procaine is a local anesthetic that preferentially stimulates limbic structures. Psychiatrically and medically healthy, age-matched women (n = 15, 33.2 +/- 6.9 years) and men (n = 15, 32.8 +/- 6.9 years) were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Using voxel-based analyses (P < 0.001), males significantly activated the bilateral insular cortex following procaine, whereas females more strongly activated the bilateral anterior and mesial temporal cortex. Both groups demonstrated significant anterior cingulate activation. Subjective responses to procaine did not significantly differ between the men and women. To our knowledge, this is the first report demonstrating gender-specific responses in limbic activation following a pharmacologic challenge. These findings suggest that men and women can activate different limbic structures following the same provocative pharmacologic stimulus, despite sharing a similar subjective experience. Studies assessing pharmacologic challenges of limbic system structures should consider gender as a critical variable in assessing biologic responsiveness.

Adult↗

PubMedDate not supplied

The safety of adenosine pharmacologic stress testing in patients with first-degree atrioventricular block in the presence and absence of atrioventricular blocking medications.

BACKGROUND: Pharmacologic stress testing in conjunction with radionuclide myocardial perfusion imaging may be used in the diagnosis of coronary artery disease and risk assessment. Adenosine can cause atrioventricular nodal (AV) block during infusion. In this study, we evaluated whether patients with baseline first-degree AV block could safely undergo adenosine stress testing. METHODS AND RESULTS: We evaluated the frequency of second- and third-degree AV block in patients with baseline first-degree AV block during adenosine stress testing, in the presence and absence of AV blocking medications (digitalis, beta-blockers, diltiazem, verapamil). Six hundred consecutive patients underwent pharmacologic stress myocardial perfusion imaging with adenosine infusion at 140 microg/kg/min for 6 minutes. A total of 43 patients (7.16%) had baseline first-degree AV block (PR interval > 200 msec), and 557 patients had a baseline PR interval < 200 msec. Twenty-one of the 43 patients (48.8 %) had further prolongation of PR interval > 240 msec, compared with 58 of 557 patients (10.4%) in the control group (P < .0001). In 16 of the 43 patients (37.3 %), second-degree AV block developed, compared with 45 of 557 patients (8.0 %) in the control group (P < .0001). In 6 of the 43 patients (13.9%), third-degree AV block developed, compared with 6 of 557 patients (1.0%) in the control group (P < .0001). All types of AV block were short duration and were not associated with any specific symptoms. None of these episodes required specific treatment. The presence of AV blocking medications (digitalis, beta-blockers, diltiazem, verapamil) did not increase the incidence of AV block during adenosine infusion. CONCLUSION: In patients with baseline PR interval of more than 200 msec, the frequency of second- and third-degree AV block during adenosine stress testing was significantly higher than in patients with a normal baseline PR interval. AV blocking medications did not increase the incidence of second- and third-degree AV block during adenosine stress testing. We conclude that it is safe to perform adenosine pharmacologic stress testing in patients with baseline PR prolongation.

Adenosine↗

PubMed2000

Pharmacological property of tributyltin in vivo and in vitro.

Tributyltin (TBT), an assumed endocrine-disrupting chemical, is widely known to show harmful effects in invertebrates including the dioecious snails. As for mammals, there are several reports concerning TBT toxicology, but few indications about general pharmacology of TBT. In the present study, we comprehensively examined the pharmacological effects of TBT both in vivo and in vitro. TBT (0.3 or 1.0 mg/kg) attenuated the small intestinal propulsive activity measured by the charcoal method in vivo, and caused concentration-dependent relaxation of isolated guinea-pig ileum in vitro (1.0x10(-8)-3.0x10(-6) M). TBT induced concentration-dependent relaxation of guinea-pig trachea, which was not inhibited by pre-treatment with a beta-adrenoceptor antagonist. TBT caused a concentration-dependent contraction of rat aortae, and also evoked endothelium-dependent relaxation in the presence of an alpha-adrenoceptor antagonist. The relaxation was inhibited by a muscarinic receptor antagonist. TBT reduced the electrically evoked, sympathetic contractile responses of rat vas deferens, which were slightly prevented by an alpha(2)-adrenoceptor antagonist. These results suggest that TBT possesses diverse pharmacological properties in mammalian organs.

Journal Article↗

PubMed2003

Pharmacological prevention of cardiac risk in claudicants with ischaemic heart disease.

BACKGROUND: Claudicants rarely progress to critical limb ischaemia but have a threefold increase in mortality, mainly due to cardiac disease. Antithrombotic therapy, beta blockers, ACE inhibitors and statins have been shown to reduce mortality and cardiovascular morbidity in patients with ischaemic heart disease. AIM: To investigate secondary pharmacological prevention of ischaemic heart disease in claudicants. MATERIALS AND METHODS: We prospectively recorded comorbidity and drug treatment in 89 patients (67 men and 22 women) with a history of ischaemic heart disease recruited in a supervised exercise and lifestyle modification programme to improve claudication distance and prognosis. RESULTS: Of the 89 cases, 40 had a history of angina only and 49 of myocardial infarction. Sixteen (18%) had diabetes, 47 (53%) had hypercholesterolaemia and 52 (58%) were hypertensive. Antithrombotic therapy was prescribed to 61 patients (68.5%), 64 (72%) with a history of myocardial infarction and 27 (67.5%) with angina only (p = 1). Beta-blockers were prescribed to 12 (13.5%) patients only, seven (15%) with a history of myocardial infarction and five (12.5%) with angina only (p = 1). Of the 47 patients with hypercholesterolaemia, 29 (62%) were on a statin. CONCLUSION: Secondary pharmacological prevention of ischaemic heart disease in claudicants remains suboptimal, with only two thirds of patients receiving antithrombotic therapy and a small minority receiving beta blockers. Pharmacological prevention in claudicants should improve to reduce cardiac morbidity and mortality.

Adrenergic beta-Antagonists↗

PubMed2003

Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription.

Recent efforts to develop pharmacologic agents that restore function to mutant forms of p53 hold significant promise in cancer therapy. Here, we examine the effects of such pharmacologic activation of p53 function using a small molecule, PRIMA-1, and a model system employing a p53 protein fused to a mutant steroid binding domain of the murine estrogen receptor (p53ERtam) that renders it responsive only in the presence of 4-hydroxytamoxifen. In either case, p53 activation triggered apoptosis that was not inhibited by the presence of macromolecular synthesis inhibitors. This p53-induced, transcription-independent apoptosis is Bax dependent, proceeds in the absence of a nucleus, and involves Bax translocation and cytochrome c release. Hence, pharmacologic p53 modulators can activate a transcription-independent apoptotic program.

Animals↗

PubMed1984

The history and pharmacology of dopamine agonists.

The recognition of the dopaminergic properties of some ergot derivatives has initiated new therapeutical approaches in endocrinology as well as in neurology. The pharmacological characterization of the different ergot derivatives during the last decade has largely improved our understanding of central dopaminergic systems. Their development has yielded valuable information on the pharmacology of dopamine receptors involved in the regulatory mechanisms of prolactin secretion and in striatal functions. The clinical application of such new neurobiological concepts has underlined the therapeutical interest of such compounds either in the control of prolactin-dependent endocrine disorders or in the treatment of parkinsonism. Owing to their pharmacological profiles, dopaminergic agonists represent a valuable clinical option especially in the management of Parkinson's disease in view of the problems arising from chronic L-Dopa treatment.

Animals↗

PubMed2006

Pharmacological interventions for bipolar youth: developmental considerations.

Despite the high prevalence rate, there have been relatively few controlled studies to systematically examine pharmacological treatments for children and adolescents with bipolar disorder. We review the differences in clinical characteristics between youth and adults with bipolar disorder and the extant literature of pharmacological treatments for children and adolescents with bipolar disorder, as well as discuss the effectiveness of pharmacological interventions for treating children and adolescents who are at familial risk for developing bipolar disorder. Although the number of controlled studies of youth with manic and mixed episodes is rapidly growing, there are few studies examining treatments for depression and the prevention of recurrent affective episodes in this population. Although children and adolescents with bipolar disorder commonly present with co-occurring psychiatric disorders, such as attention-deficit/hyperactivity disorder, there are limited data to guide the treatment of these patients. Recently, studies have begun to characterize prodromal manifestations of bipolar disorder and identify early intervention strategies for treating children and adolescents with an elevated risk for developing bipolar disorder.

Adolescent↗

PubMed2001

Adrenergic pharmacology: focus on the central nervous system.

Norepinephrine and epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, appetite, and autonomic outflow. Catecholamines control these functions through activation of a family of adrenergic receptors (ARs). The ARs are divided into three subfamilies (alpha1, alpha2, and beta) based on their pharmacologic properties, signaling mechanisms, and structure. ARs in the CNS are targets for several therapeutic agents used in the treatment of depression, obesity, hypertension, and other diseases. Not much is known, however, about the role of specific AR subtypes in the actions of these drugs. In this paper, we provide an overview of adrenergic pharmacology in the CNS, focusing on the pharmacologic properties of subtype-selective AR agonists and antagonists, the accessibility of these drugs to the CNS, and the distribution of ARs in different areas of the brain.

Journal Article↗

PubMed2002

Molecular basis of the pharmacological difference between rat and human bombesin receptor subtype-3 (BRS-3).

We cloned the gene and cDNA for rat bombesin receptor subtype-3 (BRS-3) and characterized its mRNA expression pattern and pharmacological properties. Despite the high degree of sequence similarity (80% identical), rat and human BRS-3 differ markedly in their pharmacological properties. Although the natural ligand for BRS-3 is still unknown, a synthetic peptide, dY-Q-W-A-V-(beta-A)-H-F-Nle-amide (dY-bombesin), activates human BRS-3 with an EC(50) of 1.2 nM. In contrast, dY-bombesin had a very poor potency for rat BRS-3 (EC(50) = 2 microM). To understand the molecular basis of this pharmacological difference, we constructed chimeric receptors in which individual extracellular loops of rat BRS-3 were replaced with the corresponding human sequences. Switching the N-terminal region or the second extracellular loop did not significantly change receptor properties. However, switching the third extracellular loop (E3) in the rat BRS-3 resulted in a chimeric receptor (RB3-E3) that behaved almost identically to human BRS-3. RB3-E3 bound dY-bombesin with high affinity (K(i) = 1.2 +/- 0.7 nM), and was activated by dY-bombesin with high potency (EC(50) = 1.8 +/- 0.5 nM). Within the E3 loop, mutation of Y(298)E(299)S(300) to S(298)Q(299)T(300) (RB3-SQT) or of D(306)V(307)P(308) to A(306)M(307)H(308) (RB3-AMH) only partially mimicked the effect of switching the entire E3 loop, and mutation of A(302)E(303) to V(302)D(303) or of V(310)V(311) to I(310)F(311) had little effect on the dY-bombesin potency. These results indicate that the sequence variation in the E3 loop is responsible for the species difference between rat and human BRS-3, and multiple residues in the E3 loop are involved in interactions with the agonist dY-bombesin.

Amino Acid Sequence↗

PubMed2003

Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands: inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors.

The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel arylalkylpiperazines structurally related to BP897 (3) are described. In binding studies, the new derivatives were tested against a panel of dopamine, serotonin, and noradrenaline receptor subtypes. Focusing mainly on dopamine D(3) receptors, SAR studies brought to light a number of structural features required for high receptor affinity and selectivity. Several heteroaromatic systems were explored for their dopamine receptor affinities, and combinations of synthesis, biology, and molecular modeling, were used to identify novel structural leads for the development of potent and selective D(3) receptor ligands. Introduction of an indole ring linked to a dichlorophenylpiperazine system provided two of the most potent and selective ligands known to date (D(3) receptor affinity in the picomolar range). The intrinsic pharmacological properties of a subset of potent D(3) receptor ligands were also assessed in [(35)S]-GTPgammaS binding assays. Evidence from animal studies, in particular, has highlighted the dopaminergic system's role in how environmental stimuli induce drug-seeking behavior. We therefore tested two novel D(3) receptor partial agonists and a potent D(3)-selective antagonist in vivo for their effect in the cocaine-seeking behavior induced by reintroduction of cocaine-associated stimuli after a long period of abstinence, and without any further cocaine. Compound 5 g, a nonselective partial D(3) receptor agonist with a pharmacological profile similar to 3, and 5p, a potent and selective D(3) antagonist, reduced the number of active lever presses induced by reintroduction of cocaine-associated stimuli. However, 5q, a highly potent and selective D(3) partial agonist, did not have any effect on cocaine-seeking behavior. Although brain uptake studies are needed to establish whether the compounds achieve brain concentrations comparable to those active in vitro on the D(3) receptor, our experiments suggest that antagonism at D(2) receptors might significantly contribute to the reduction of cocaine craving by partial D(3) agonists.

Animals↗