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PubMed1975

N-trifluoroacetyladriamycin-14-valerate, an analog with greater experimental antitumor activity and less toxicity than adriamycin.

N-Trifluoroacetyladriamycin-14-valerate (AD 32), an analog of adriamycin, exhibits significantly greater antitumor activity than does adriamycin or daunorubicin in two experimental mouse tumor systems under similar assay conditions (C57BL X DBA/2 F1 male mice, agents administered i.p. each day for Days 1 to 4). Against the P388 leukemia at optimal dosages, AD 32 gave a +429% increase in median life-span with 3 of 5 60-day survivors compared to +132% for adriamycin (no 30-day survivors). In the L1210 leukemia system, AD 32 at several dosages consistently and reproducibly effected an increase in lifespan in excess of 445%, with a high percentage of 60+-day survivors compared to adriamycin (+42 to +54% ILS; no 30-day survivors). The reduced toxicity of AD 32 was evidenced by its optimal dose range, which is significantly greater than the lethal dose for 100% of mice of adriamycin, and by its lack of delayed toxicity. In vitro, AD 32 was somewhat less effective than was adriamycin in inhibiting the growth of CCRF-CEM cells; enzymatic conversion of AD 32 by cell-free culture medium was not observed. The unique growth-inhibitory properties of this analog indicate that the therapeutic effectiveness of the anthracycline antitumor antibiotics can be retained or enhanced by substitution on the glycosidic amino group.

Animals↗
PubMed2001

Climodien (estradiol valerate 2 mg plus dienogest 2 mg) is safe and effective in the treatment of postmenopausal complaints.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of continuous combined hormone replacement therapy (HRT) with Climodien (estradiol valerate 2 mg plus dienogest 2 mg). DESIGN: Open, multinational, multicenter, non-controlled phase III study. PARTICIPANTS: A total of 1501 women aged 52-65 years with postmenopausal symptoms of sufficient severity to require treatment. METHODS: Eligible patients were treated with Climodien for 12 treatment cycles (48 weeks), with assessments of efficacy, safety and tolerability (adverse events) at 8, 24 and 48 weeks. Efficacy was assessed using the Kupperman index. Safety assessments included endovaginal sonography, safety endometrial biopsies, mammography, physical and gynecological examination, vital signs, prothrombotic factors and routine laboratory safety parameters. RESULTS: The Kupperman index improved with increasing duration of treatment, accompanied by an improvement in self-reported patient well-being. Individual climacteric symptoms such as hot flushes and psychonervous disorders also improved. The most pronounced improvement was seen in women who had not previously used HRT. The incidence of breakthrough bleeding declined over time, resulting in complete amenorrhea in 86.2% of the patients after 12 cycles of treatment. Furthermore, total and low-density lipoprotein (LDL) cholesterol levels decreased and high-density lipoprotein (HDL) cholesterol levels increased. Decreases in alkaline phosphatase, pyridinoline and deoxypyridinoline demonstrated the inhibitory action of estradiol on bone resorption. Endometrial thickness remained almost constant, and the incidence of serious endometrial findings was similar to that in untreated women. CONCLUSIONS: Continuous combined estrogen-progestin therapy with Climodien is effective, safe and well tolerated in postmenopausal women, with a profile and incidence of adverse events consistent with those of existing HRT preparations.

Aged↗
PubMed2002

[Clinical effects of hormone replacement therapy with estradiol valerate and cyproterone acetate in perimenopausal women].

BACKGROUND: In perimenopause many women complain of psychogenic and organic disorders often connected with initial and increasing levels of hypoestrogenism. In this study we evaluated the effects of hormone replacement therapy (HRT) in symptomatic women in perimenopause. METHODS: We enrolled 100 healthy and symptomatic women who were randomly distributed to two groups for a 12-month study. Group A: 50 patients received HRT with estradiol valerate and cyproterone acetate (Pausene(R)); Group B: 50 patients were used as a control group (treated with Cacit Vitamin D30(R)). A number of clinical and instrumental tests were performed at 0, 6 and 12 months to evaluate any changes in vasomotor and urogenital symptoms, bone and serum homeostasis and possible sexual disorders. The statistical analysis was performed using the c2 test. RESULTS: The group of women receiving HRT showed a significant reduction in vasomotor clinical symptoms (p<0.001) and sexual disorders (p<0.002); this was not reflected in the control group where libido decreased steadily with apparent slight improvements only at the end of the study. The urogenital disorders disappeared almost completely in Group A, whereas they diminished in Group B. HRT patients also showed a slight increase (p<0.001) in the initial value of BMD (bone mineral density), a reduction in the marker for bone turnover and an improved lipid profile (p<0.05). These changes were unfortunately not noted in Group B. CONCLUSIONS: On the basis of these results we conclude that HRT appeared to have a beneficial effect on perimenopausal clinical symptoms over the 12-month period, leading to marked improvements in the psychophysical wellbeing of symptomatic women in perimenopause.

Climacteric↗
PubMed2002

Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14-valerate with the C1-regulatory domain of protein kinase C: structural requirements, isoform specificity, and correlation with drug cytotoxicity.

Anthracycline antibiotics like doxorubicin (DOX) are known to exert their antitumor effects primarily via DNA intercalation and topoisomerase II inhibition. By contrast, the noncross-resistant cytoplasmically localizing DOX analogue, N-benzyladriamycin-14-valerate (AD 198), only weakly binds DNA and does not inhibit topoisomerase II, yet it displays superior antitumor activity, strongly suggesting a distinct cytotoxic mechanism. In recent modeling studies, we reported a structural similarity between AD 198 and commonly accepted ligands for the C1-domain of protein kinase C (PKC), and we hypothesized that the unique biological activity of AD 198 may derive, in part, through this kinase. Consistent with this hypothesis, the present biochemical studies demonstrate that AD 198 competes with [3H]phorbol-12,13-dibutyrate ([3H]PDBu) for binding to phorbol-responsive PKC isoforms, the isolated C1b domain of PKC-delta (delta C1b), and the nonkinase phorbol ester receptor, beta2-chimaerin. In NIH/3T3 cells, AD 198 competitively blocks PKC activation by C1-ligands. Importantly, neither DOX nor N-benzyladriamycin, the principal AD 198 metabolite, inhibits basal or phorbol-stimulated PKC activity or appreciably competes for [3H]PDBu binding. In CEM cells, structure activity studies with 14-acyl congeners indicate that the rapid induction of apoptosis correlates with competition for [3H]PDBu binding, strongly implicating phorbol-binding proteins in drug activity. Collectively, these studies support the conclusion that AD 198 is a C1-ligand and that C1-ligand receptors are selective drug targets. These studies provide the impetus for continuing efforts to understand the molecular basis for the unique biological activity of AD 198 and provide for the design of analogues with improved affinity for C1-domains and potentially greater antitumor activity.

3T3 Cells↗
PubMed2002

[Prevention of bone loss by estradiol valerate combined with medroxyprogesterone acetate among postmenopausal women with osteopenia].

OBJECTIVE: To observe the efficacy of estradiol valerate (E(2)V) combined with medroxyprogesterone acetate (MPA) in prevention of bone loss among postmenopausal women with osteopenia. METHODS: Ninety-two women 1 to 8 years after menopause with osteopenia were randomly divided into 4 groups: 1) control group: 23 cases, taking calcium carbonate (Ca) 400 mg/d+ vitamin D 200 IU/D; 2) treatment group 1: 24 cases, taking E(2)V 1.0 mg/d+ MPA 2 mg/d+ Ca 400 mg/d; 3) treatment group 2: taking E(2)V 1.0 mg/d+ MPA 2 mg/d+ Ca 400 mg/d+ vitamin D 200 IU/d; and 4) treatment group 3: taking E(2)V 1.5 mg/d+ MPA 2 mg/d+ Ca 400 mg/d+ vitamin D 200 IU/d. The bone mineral density (BMD) of L(2- 4) and neck of femur was measured by DEXA method, and the bone metabolic markers such as serum alkaline phosphatase (ALP) and urine Ca/Cr and Ntx/Cr were examined just before the drug administration and 6, 12, and 18 months after the beginning of experiment. Vaginal bleeding and breast tenderness were recorded by the subjects themselves and examined by investigators. RESULTS: Seventy-eight subjects (84.5%) were followed up for I year and 77 of them (83.7%) were followed up for 1.5 years. The fasting morning Ca/Cr remained almost unchanged in the control group, and decreased by 43.8%, 33.3%, and 33.3% by the third month respectively and then remained unchanged in the treatment groups 1, 2, and 3. The urine Ntx/Cr decreased mildly but insignificantly in the control group (P > 0.05), and decreased since the 3rd month by 42.2%, 53.2%, and 29.1% respectively in the treatment groups 1 approximately 3 and then decreased very slowly. The ALP remained almost unchanged in the control group, and decreased by 6.8%, 17.0%, and 16.4% by the 6th months respectively and by 14.2%, 17.9%, and 28.8% by the 12th month and then remained almost unchanged in the treatment groups 1 approximately 3. The BMD of L2-4 increased by 7.1% +/- 4.6%, 6.8% +/- 5.3%, and 9.0% +/- 4.0% in the treatment 1 approximately 3 by the 18th month. The BMD of neck of femur increased by 4.1% +/- 3.2%, 4.0% +/- 5.9%, and 5.9% +/- 4.8% in the treatment 1 approximately 3 by the 18th month. Fracture occurred in 2 cases of the control group and 2 cases of the treatment group because of accidents. The vaginal bleeding rate was the highest in the treatment group 3 (47.4%). The breast tenderness rates were 27.3% approximately 47.6% in the 3 treatment groups. CONCLUSION: Administration of E(2)V I mg/d combined with MPA 2 mg/d is an optional regimen for postmenopausal women with intact uterine.

Adult↗
PubMed1976

Differences in cellular uptake and cytofluorescence of adriamycin and N-trifluoroacetyladriamycin-14-valerate.

Adriamycin-specific fluorescence appears slowly in living cells and is localized in nuclei and chromosomes. N-Trifluoroacetyladriamycin-14-valerate, a recently synthesized adriamycin analog, differs from the parent anthracycline in the rapid appearance of its fluorescence in the cytoplasm of living cells and the lack of any fluorescent binding to nuclei and chromosomes.

Cell Line↗
PubMed1992

Synchronization of estrus in dairy goats given norgestomet and estradiol valerate at various stages of the estrous cycle.

Dairy goats were given subcutaneous implants with 3 mg of norgestomet (NOR) and IM injections of 0.625 mg of estradiol valerate and 0.375 mg of norgestomet on day 0 of the estrous cycle (estrus; NOR 0, n = 18), on postestrus day 4 (NOR 4, n = 18), or on postestrus day 11 (NOR 11, n = 15). Ear implants were removed after 9 days. Mean (+/- SE) hours from removal of ear implants to onset of estrus and proportion of goats responding were 36 +/- 3.8 and 83%, 33 +/- 4.0 and 61%, and 36 +/- 2.7 and 93% for groups NOR 0, NOR 4, and NOR 11, respectively. There were no significant differences between treatment groups in time to onset of estrus. The percentage of goats in group NOR 11 that had signs of estrus was significantly greater than the percentage of goats in group NOR 4. Of the goats in groups NOR 0, NOR 4, and NOR 11 that had signs of estrus, 53, 55, and 86%, respectively, had onset of behavioral estrus between 24 and 48 hours after implant removal. All goats that had signs of estrus had onset of behavioral estrus between 12 and 72 hours after implant removal. Mean (+/- SE) hours from removal of ear implants to time of peak concentrations of luteinizing hormone (LH) were 49 +/- 4.1, 49 +/- 3.8, and 49 +/- 4.0 for groups NOR 0, NOR 4, NOR 11, respectively (not different). The percentage of goats in group NOR 11 that had LH peaks was significantly greater than the percentage of goats in group NOR 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Clinical efficacy and safety of combined estradiol valerate and dienogest: a new no-bleed treatment.

A combination of 2 mg estradiol valerate with 2 mg dienogest (E2V/DNG) (Climodien, Schering AG, Berlin, Gemany) is the first continuous combined postmenopausal hormone replacement therapy (HRT) preparation to contain a progestogen with substantial antiandrogenic activity. A study of its clinical efficacy and safety in a comparative study versus a combination of 2 mg estradiol with 1 mg norethisterone acetate (E2/NETA) has shown both preparations to be highly effective in achieving a rapid response in women with postmenopausal symptoms, in terms of hot flushes and the Kupperman index. Biopsy and ultrasound studies have demonstrated that E2V/DNG quickly and effectively achieved endometrial atrophy in the vast majority of subjects, suggesting a protective role in endometrial proliferation. Data on PP-14 (glycodelin) levels may indicate that E2V/DNG is even more effective than E2/NETA in maintaining endometrial atrophy. No-bleed rates with E2V/DNG at 1, 6 and 12 months were at least as favorable as those with other standard HRT products, with evidence that the no-bleed state is attained more quickly with E2V/DNG. The proportions of women with the no-bleed state in a large-scale study (n = 1501) at 1, 6 and 12 months were 71.8%, 76.6% and 86.4%, respectively. Women with irregular bleeding before treatment responded to E2V/DNG in a manner similar to those without bleeding; this concordance was especially marked after five cycles of treatment. In the comparative study, the mean number of days of bleeding over 12 cycles was significantly lower for E2V/DNG than for E2/NETA. Overall, the profiles of adverse events recorded in clinical use were similar in the two preparations, whilst the safety profile of E2V/DNG in the large-scale study was similar to that of other HRT preparations and gave no cause for clinical concern. The 2 mg E2V/2 mg DNG preparation was associated with a favorable lipid profile, whilst a similar combination (2 mg E2V/3 mg DNG) showed no impact on carbohydrate metabolism or hemostasis, compared to placebo. In summary, 2 mg E2V/2 mg DNG is a novel continuous combined HRT preparation that is effective in treating postmenopausal symptoms rapidly, and has a highly favorable bleeding profile. Studies of the safety of 2 mg E2V/2 mg DNG in clinical use have uncovered no factors likely to be disadvantagous in comparison with other HRT products in widespread use.

Clinical Trials as Topic↗
PubMed2004

[Effect and tolerability of sequential administration of estradiol valerate and medroxyprogesterone acetate on menopausal symptoms, hormonal profile and biochemical markers in climacteric women].

UNLABELLED: Hormonal replacement therapy is the gold standard in the treatment and prophylaxis of menopausal symptoms and osteoporosis. THE AIM: Of the study was to assess changes in climacteric symptoms, hormonal profile and biochemical parameters during sequential hormonal replacement therapy in climacteric women 19 women aged 46-61 years old was included into the study. We evaluated Kuppermann's index, serum concentration of estradiol, FSH, morphology of the blood, lipids and haemostatic parameters. RESULTS: The menopausal symptoms significantly decreased. Lipids levels, haemostatic parameters and morphological parameters of the blood didn't change. CONCLUSION: The sequential hormonal replacement therapy with estradiol valerate and medroxy-progesterone acetate is efficient and safe.

Aged↗
PubMedDate not supplied

Permanent induction of morphological abnormalities in the penis and penile skeletal muscles in adult rats treated neonatally with diethylstilbestrol or estradiol valerate: a dose-response study.

This study evaluated the effects of neonatal exposure to different doses of diethylstilbestrol (DES) or estradiol valerate (EV) on penile morphology, penile skeletal muscles, and fertility. Male pups received DES or EV at a dose of 10 microg, 1 microg, 100 ng, 10 ng, or 1 ng per rat on alternate days from postnatal days 2-12. Fertility was tested at 120 days, and tissues were examined at 150 days. Generally, DES and EV induced similar effects within the 10- and 1-microg groups. Fertility was reduced to 0; the weight, length, and diameter of the penis and the weight of penile skeletal muscles, especially bulbocavernosus muscle, were decreased (P <.05) in a dose-dependent manner; the preputial sheath was partially released or its release was delayed; testicular descent was delayed; and the cavernous spaces and smooth muscle cells in the corpora cavernosa penis were replaced by fat cells. Conversely, all of the above parameters were similar in controls and the lower dose groups, except in the 100-ng DES group, in which 4 of 7 males did not sire pups (compared with 1 of 7 in controls and 2 of 6 in the 100-ng EV group). The loss of fertility in these 4 males of the DES group and 1 male of the EV group was associated with partial release of the preputial sheath and abnormal penile morphology. Plasma testosterone was reduced (P <.05) in the 100-ng and higher dose groups for DES and EV. Hence, neonatal exposure to DES or EV at a cumulative dose of 600 ng per rat or more lowers fertility, which is associated with permanent alterations in penile morphology and penile skeletal muscles and decreased testosterone.

Animals↗
PubMed1991

[Determination of megestrol acetate and estradiol valerate in injection of microencapsulated compound megestrol acetate by secondary derivative spectrophotometry].

The paper reports the simultaneous determination of megestrol acetate and estradiol valerate in the injection of microencapsulated compound megestrol acetate by secondary derivative spectrophotometry. The experimental results showed that the average recoveries of the two drugs were 98.8% and 98.0%, respectively, and that the coefficients of variation were 0.71% and 1.81%, respectively.

Capsules↗
PubMed1990

The effects of long-term using once-a-month injectable contraceptive norethisterone enanthate/estradiol valerate on coagulation in the Chinese.

Sixty-four Chinese women were studied for the effects of injecting once-a-month contraceptive norethisterone enanthate/estradiol valerate between 2 to 4 1/2 years on certain coagulation and fibrinolytic parameters, and 59 women not receiving any steroidal contraception were controls. In both groups there was no significant change in PT, fibrinogen, factor X activity, AT III antigen, AT III activity and fibrinolytic activity expressed by euglobulin lysis time. There was no significant difference in mean levels of factor VIIIR:Ag between the two groups, although a sub-group women in treatment group had higher than accepted levels of factor VIIIR:Ag.

Adult↗
PubMed1989

A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters.

Ethinyl estradiol (EE) is still used to some extent as hormonal replacement therapy (HRT) in the climacteric period. As regards oral contraception, it is well known that the induced increase in cardiovascular disease is related to the estrogen component (invariably EE) in a dose-related fashion. Considerably lower doses of EE are needed in HRT compared to oral contraception. To delineate and compare effects of EE and estradiol valerate (E2V) in doses needed in HRT on haemostasis parameters, 24 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (10 micrograms EE and 2 mg E2V daily) are the lowest which eliminate climacteric symptoms in a majority of women. Unlike E2V, EE caused increased levels of factor VII:Ag, factor VIII:C and beta-thromboglobulin, which may be changes towards hypercoagulability. Both estrogens decreased the AT III activity. Long-term administration (6 + 12 w) of the estrogens induced further changes in haemostatic parameters. 10 micrograms EE increased factor VII:Ag in contrast to 2 mg E2V. Furthermore both estrogens increased factor VIII:C and factor II-VII-X. A decrease in platelet count was induced by both EE and E2V. Oral contraception and adjuvant estrogen therapy in men with prostatic carcinoma are known to imply an increased cardiovascular risk. It is noteworthy that the pattern of changes in haemostatic parameters induced by as little as 10 micrograms of EE is the same as seen after the administration of combined oral contraceptives or the substantially higher doses of EE given as adjuvant therapy to men with prostatic carcinoma.

Adult↗
PubMed1987

[Behavior the lipid spectrum following complete ovariectomy and subsequent substitution with estradiol valerate or norethisterone acetate].

In a prospective trial the effects of oophorectomy and following administration of estradiol valerate (2,0 mg/day) or norethisterone acetate (5,0 mg/day) on the blood lipids were investigated during the late postoophorectomy time. After complete ovarectomy 52 women (42-49 years old) were randomized in two groups and substituted with these steroids from the 7. to 12. month after operation. Before total estrogen excretion/24 h urine, serum levels of estradiol and testosterone and the maturation value were studied. The blood levels of total-, HDL- nnd LDL cholesterol and triglycerides were markedly higher 2 and 6 months after castration than before. Norethisterone acetate depressed transitorily the total cholesterol and longer the HDL cholesterol, the triglycerides were increased 6 months after administration. A long lasting norethisterone acetate substitution in postmenopausal women should be below 5 mg/day.

Adult↗
PubMed1986

Modulation of adriamycin and N-trifluoroacetyladriamycin-14-valerate induced effects on cell cycle traverse and cytotoxicity in P388 mouse leukemia cells by caffeine and the calmodulin inhibitor trifluoperazine.

1,3,7-Trimethylxanthine "caffeine" (CAF) is reported to induce a differential effect on the cytotoxicity of the DNA intercalators actinomycin-D versus Adriamycin (ADR). In the present study the effect of caffeine and/or trifluoperazine in modulating cell cycle traverse, drug accumulation, and cytotoxicity of anthracyclines was evaluated. The survival in soft agar of P388 mouse leukemia cells treated with ADR (0.05-0.25 micrograms/ml) alone for 1 h was 1.2- to 3-fold lower when the cells were incubated for 24 h in drug-free medium versus medium supplemented with 2 mM CAF. In contrast, for P388 cells treated with ADR in the presence of 2 mM CAF for 1 h and subsequently incubated for 24 h in the absence or presence of 2 mM CAF, cell killed based on colony formation in soft agar was 2- to 20-fold lower than in ADR-treated cells never exposed to 2 mM CAF. In cells treated continuously for 24 h with ADR (0.01-0.05 micrograms/ml) or the DNA nonbinding ADR analogue N-trifluoro-acetyladriamycin-14-valerate (AD32) (0.05 and 0.1 micrograms/ml) the survival in soft agar was 3- to 20-fold higher in the presence versus the absence of 2 mM CAF. The decreased cytotoxicity in cells treated with ADR or AD32 in the presence of CAF was accompanied by a significant reduction in the accumulation of cells in G2. However, in cells treated with ADR or AD32 in the presence of 2 mM CAF plus 5 microM trifluoperazine the decreased G2 accumulation was not accompanied by a reduction in anthracycline cytotoxicity. The modulation by CAF of ADR and AD32 cytotoxicity did not correlate with decreased cellular ADR and AD32 accumulation. Results from this study indicate that CAF markedly reduces the cytotoxicity of ADR or AD32 and trifluoperazine circumvents the effects of CAF.

Animals↗
PubMed1979

Initial clinical evaluation of N-trifluoroacetyladriamycin-14-valerate (AD-32), an adriamycin analog.

N-Trifluoroacetyladriamycin-14-valerate (AD-32) is superior to Adriamycin in murine L1210 and P388 leukemias and in a number of solid tumor systems, including Ridgway osteogenic sarcoma and Lewis lung carcinoma. In preclinical toxicology studies, AD-32 was less toxic than Adriamycin in both tumor- and non-tumor-being mice and in rabbits. An initial clinical trial was carried out in 23 patients who received a total of 74 courses of AD-32 over a dose range of 100--700 mg/m2 administered at 21-day intervals. Hydrocortisone given during the period of infusion prevented all clinical manifestations of acute toxicity. The AD-32 dose-limiting toxicity, leukopenia, was comparable to that of Adriamycin at a dose of 10:1, but at these equivalently myelosuppressive doses, AD-32 induced less gastrointestinal toxicity and alopecia than Adriamycin and it did not cause local tissue damage following inadvertent paravenous extravasation. Although two responses are reported, the therapeutic activity of AD-32 cannot be assessed because of an inadequate number of patients in any given tumor type. A phase II study is being initiated at a dose of 600 mg/m2 given at 21-day intervals.

Doxorubicin↗
PubMed1978

Hepatobiliary metabolism and excretion of adriamycin and N-trifluoroacetyladriamycin-14-valerate in the rat.

In connection with mechanism of action studies with N-trifluoroacetlyadriamycin-14-valerate (AD 32), a superior Adriamycin (ADR) analog under development in these laboratories, serial bile samples were collected from male Sprague-Dawley rats given a single i.v. dose of either ADR (4 mg/kg) or AD 32 (20 mg/kg) and were analyzed for anthracyclines by thin-layer chromatography-fluorometry and high-performance liquid chromatography. For ADR, 20% of the administered dose was accounted for at 24 hr, whereas 80% of the AD 32 dose were excreted into the bile by this time. ADR underwent little biotransformation; 80% of the 48-hr cumulative fluorescence excretion was attributable to unchanged drug, one-half the remainder was adriamycinol, and the balance was polar conjugates. In contrast, AD 32 underwent extensive metabolism to N-trifluoracetyladriamycin, N-trifluoroacetyladriamycinol, and polar conjugates, mostly glucuronides of N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol. Based on direct and indirect evidence, ADR was not a metabolite of AD 32.

Animals↗