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Compatibility and stability of linezolid injection admixed with three quinolone antibiotics.

OBJECTIVE: To evaluate the physical compatibility and chemical stability of linezolid 200 mg/100 mL admixed with ciprofloxacin 400 mg, ofloxacin 400 mg, and levofloxacin 500 mg for seven days at 4 and 23 degrees C. METHODS: The test samples were prepared by adding the required amount of the quinolone antibiotic to bags of linezolid injection. Evaluations for physical and chemical stability were performed initially and after one, three, five, and seven days of storage at temperatures of 4 and 23 degrees C. Physical stability was assessed using visual observation in normal light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drugs was evaluated by using stability-indicating HPLC analytical techniques. RESULTS: The linezolid admixtures with levofloxacin and ofloxacin were clear and pale yellow when viewed in normal fluorescent room light, and slightly hazy with a green cast when viewed using a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. HPLC analysis found no loss of the drugs in any sample stored at either temperature throughout the study. The linezolid admixtures with ciprofloxacin stored at room temperature (23 degrees C) were clear and nearly colorless in normal room light and when viewed using a Tyndall beam. They exhibited little or no change in measured turbidity or particulate content during the study period. HPLC analysis found no loss of either drug in seven days. However, the refrigerated samples were only compatible for 24 hours and developed a gross white precipitate thereafter. CONCLUSIONS: Admixtures of linezolid 200 mg/100 mL with levofloxacin 500 mg and with ofloxacin 400 mg were physically compatible and chemically stable for at least seven days stored at 4 and 23 degrees C. Admixtures of linezolid with ciprofloxacin 400 mg were compatible and stable for seven days at 23 degrees C, but ciprofloxacin precipitation occurred after 24 hours stored under refrigeration. Linezolid/ciprofloxacin admixtures should not be stored under refrigeration.

Acetamides↗

Does airway pressure release ventilation alter lung function after acute lung injury?

BACKGROUND: During airway pressure release ventilation (APRV), tidal ventilation occurs between the increased lung volume established by the application of continuous positive airway pressure (CPAP) and the relaxation volume of the respiratory system. Concern has been expressed that release of CPAP may cause unstable alveoli to collapse and not reinflate when airway pressure is restored. OBJECTIVE: To compare pulmonary mechanics and oxygenation in animals with acute lung injury during CPAP with and without APRV. DESIGN: Experimental, subject-controlled, randomized crossover investigation. SETTING: Anesthesiology research laboratory, University of South Florida College of Medicine Health Sciences Center. SUBJECTS: Ten pigs of either sex. INTERVENTIONS: Acute lung injury was induced with an intravenous infusion of oleic acid (72 micrograms/kg) followed by randomly alternated 60-min trials of CPAP with and without APRV. Continuous positive airway pressure was titrated to produce an arterial oxyhemoglobin saturation of at least 95% (FIO2 = 0.21). Airway pressure release ventilation was arbitrarily cycled to atmospheric pressure 10 times per minute with a release time titrated to coincide with attainment of respiratory system relaxation volume. MEASUREMENTS: Cardiac output, arterial and mixed venous pH, blood gas tensions, hemoglobin concentration and oxyhemoglobin saturation, central venous pressure, pulmonary and systemic artery pressures, pulmonary artery occlusion pressure, airway gas flow, airway pressure, and pleural pressure were measured. Tidal volume (VT), dynamic lung compliance, intrapulmonary venous admixture, pulmonary vascular resistance, systemic vascular resistance, oxygen delivery, oxygen consumption, and oxygen extraction ratio were calculated. MAIN RESULTS: Central venous infusion of oleic acid reduced PaO2 from 94 +/- 4 mm Hg to 52 +/- 9 mm Hg (mean +/- 1 SD) (p < 0.001) and dynamic lung compliance from 40 +/- 6 mL/cm H2O to 20 +/- 6 mL/cm H2O (p = 0.002) and increased venous admixture from 13 +/- 3% to 32 +/- 7% (p < 0.001) in ten swine weighing 33.3 +/- 4.1 kg while they were spontaneously breathing room air. After induction of lung injury, the swine received CPAP (14.7 +/- 3.3 cm H2O) with or without APRV at 10 breaths per minute with a release time of 1.1 +/- 0.2 s. Although mean transpulmonary pressure was significantly greater during CPAP (11.7 +/- 3.3 cm H2O) vs APRV (9.4 +/- 3.8 cm H2O) (p < 0.001), there were no differences in hemodynamic variables. PaCO2 was decreased and pHa was increased during APRV vs CPAP (p = 0.003 and p = 0.005). PaO2 declined from 83 +/- 4 mm Hg to 79 +/- 4 mm Hg (p = 0.004) during APRV, but arterial oxyhemoglobin saturation (96.6 +/- 1.4% vs 96.9 +/- 1.3%) did not. Intrapulmonary venous admixture (9 +/- 3% vs 11 +/- 5%) and oxygen delivery (469 +/- 67 mL/min vs 479 +/- 66 mL/min) were not altered. After treatment periods and removal of CPAP for 60 min, PaO2 and intrapulmonary venous admixture returned to baseline values. DISCUSSION: Intrapulmonary venous admixture, arterial oxyhemoglobin saturation, and oxygen delivery were maintained by APRV at levels induced by CPAP despite the presence of unstable alveoli. Decrease in PaO2 was caused by increase in pHa and decrease in PaCO2, not by deterioration of pulmonary function. We conclude that periodic decrease of airway pressure created by APRV does not cause significant deterioration in oxygenation or lung mechanics.

Animals↗

Stability and compatibility of ganciclovir sodium in 5% dextrose injection over 35 days.

The stability and compatibility of ganciclovir sodium in 5% dextrose injection over 35 days were assessed. Nine admixtures of ganciclovir sodium 1, 5, and 10 mg/mL in 5% dextrose injection were aseptically prepared. Immediately thereafter, six samples were aseptically withdrawn from each admixture into sterile collection tubes. Three of the samples were frozen for stability-indicating high-performance liquid chromatographic (HPLC) assay at a later date, and the other three were immediately assessed for pH. Each admixture was also assessed visually for color change, turbidity, gas evolution, and precipitation. The admixtures were stored in the dark at 4-8 degrees C and sampled at 10 and 35 days. There was no significant loss of ganciclovir over the 35-day study period. No admixture at any time contained less than 93.4% or more than 103.7% of its initial ganciclovir concentration. There were no appreciable pH changes, and there was no evidence of visual incompatibility. Ganciclovir sodium 1, 5, and 10 mg/mL in 5% dextrose injection was stable for at least 35 days when stored in the dark at 4-8 degrees C.

Chromatography, High Pressure Liquid↗

[Infusion mixtures--study of clinical practice in Austria].

Options in parenteral therapy increasingly require administration of several medications simultaneously. Very little is known about the compatibility and pharmacological stability of such mixtures. We investigated how widespread this practice is, which carrier solutions are most commonly used, and whether specific medication mixtures ('cocktails') or constant formulations for TPN are applied. Upon our request, physicians and nursing staff of 54 general hospital wards (19 surgical, 18 internal medicine, 17 intensive care) in 17 Austrian hospitals recorded the parenteral admixtures for one week under the supervision of a hospital pharmacist. We found that: 1. Admixing is commonly practiced in all wards. In all but one of the wards two or even more medications are added into one single infusion. 2. Carrier solutions were: Dextrose/fructose (87% of the wards), electrolytes (90%), amino acids (40%), fat emulsions (26%), colloids (14.8%), albumin (5.5%) and Solcoseryl (5.5%). 3. Fixed combinations for i.v. therapy are practiced in 70% of the wards (mostly analgetics with corticosteroids or vitamins) 4. In almost half of the units constant formulations for TPN exist (46%). Only few of the combinations named have been investigated or tested for stability. The compatibility of most of the admixtures is unknown, while a few are clearly incompatible. Admixtures to one of the carrier solutions (Solcoseryl) are known to have caused serious complications before. For several admixtures, conflicting data about compatibility were found in the literature. The theoretical basis for incompatibilities is discussed together with some typical examples. Also some rules for admixtures are given. Questions concerning the compatibility of simultaneous parenteral drug applications are too specific to be answered for most physicians. Advice and counseling on this subject should become a new task for clinical pharmacists.

Austria↗

Soluble and Lente human insulin mixtures in normal man.

The interaction between soluble (Actrapid HM) and Lente (Monotard HM) human insulin preparations was examined in normal subjects. Incremental plasma insulin levels were determined following the subcutaneous administration of 6 U of soluble insulin admixed with 0.14 ml soluble insulin diluting medium, or 0.14 ml Lente diluting medium and injected either immediately or 5 min after preparation. For comparison separate but simultaneous injections of soluble (6 U) and Lente insulin (14 U) were administered subcutaneously. All injection volumes were identical. The incremental insulin levels were significantly greater between 60 and 90 min (p less than 0.05-0.01) following the administration of soluble insulin admixed with its own medium compared to the soluble insulin/Lente medium admixtures injected immediately and 5 min after preparation. There was no difference, however, in the plasma insulin profiles between the two soluble insulin/Lente medium schedules. The separate simultaneous administration of soluble and Lente insulin resulted in significantly higher plasma insulin levels at 30 and 90 min (p less than 0.05) when compared to the admixture injected immediately after preparation and from 30-120 min (p less than 0.05-0.01) compared to the admixture injected after 5 min. The two soluble/Lente insulin admixtures achieved similar plasma insulin profiles. Therefore when soluble human insulin is admixed with Lente human insulin and administered by subcutaneous injection immediately after admixing there is a significant reduction in the plasma insulin levels during the first 90 min in contrast to when the two preparations are given simultaneously by separate injection. Delaying the injection of the admixture for 5 min results in significantly lower insulin levels up to 120 min. These differences are reflected in the hypoglycaemic responses observed.

Adult↗

The effects of cardiopulmonary bypass upon pulmonary gas exchange.

Cardiac output, venous admixture, physiological dead space, blood gas tensions, inspired gas distribution, and other respiratory variables were measured in 10 patients breathing both air and oxygen before and on five occasions up to 10 days after coronary artery vein-graft operations under cardiopulmonary bypass with moderate hypothermia. Cardiac output was unchanged at 8 hours but fell 8 percent by 22 hours. Thereafter it progressively increased and at 10 days was higher than before the operation. Venous admixture rose to a maximum at 28 to 48 hours, postoperatively, but the increase was inversely related to the magnitude of preoperative admixture. The part played by airway and alveolar closure in determining venous admixture is discussed. While admixture increased, the nitrogen-clearance curve improved, presumably due to progressive "dropout" of the worst-ventilated regions. Physiological dead space fell to a minimum at 28 hours after operation; this was attributed to a fall in the end-inspiratory position consequent upon a reduction in both functional residual capacity and tidal volume. There was an increase in ventilation after operation, and this persisted at 10 days; it appeared to be due to reflex stimulation from the lungs and chest wall.

Adolescent↗

Cost analysis of mixing clindamycin and aminoglycosides.

Data were collected to determine if cost savings could be achieved by mixing clindamycin and aminoglycosides (gentamicin or tobramycin) in the same minibag for intravenous administration. The following issues were investigated: drug and supply costs associated with combination admixtures, pharmacy labor costs, and waste. Over a 17-month period, 1961 combination admixtures were prepared; 62 of these doses were wasted. Drug cost savings of $128.15, supply cost savings of [4719.48, and labor cost savings of [1878.40 were achieved, with an overall cost savings (minus waste) of $5658.01. Overall waste was similar with the combined admixture service and the preparation of separate doses, and the aminoglycoside pharmacokinetic dosing service did not substantially affect use of the combination admixtures. The clindamycin and aminoglycoside admixture system was effective in reducing supply and labor costs.

Aminoglycosides↗

Evaluating aseptic technique of pharmacy personnel.

A procedure for validating the effectiveness of a training program in aseptic technique for admixture personnel and for monitoring the aseptic technique of those trained is described. Double-strength soybean casein digest broth was prepared as the culture media. Technicians were instructed to prepare 50 sample i.v. admixtures after the structured one-week orientation and training period. The sample admixtures were cultured for sterility by a total-culturing method. An ongoing random-sampling plan was implemented to monitor the technique of the trained technicians. Six technicians completed the orientation program, and five compounded the validation admixtures aseptically. The ongoing monitoring revealed that the technicians who were validated have continued to perform at acceptable levels. This program validated that the personnel had adequate training in aseptic technique and the necessary skills for performing the aseptic manipulations required in i.v. admixture compounding.

Antisepsis↗

Factors affecting insulin adherence to type I glass bottles.

Some physicochemical factors that could account for insulin adherence to type I glass bottles from admixtures of insulin with 5% dextrose (D5W) and 0.9% sodium chloride (NS) injections were studied. Samples of three volumes of NS or D5W containing insulin I 125 were mixed in three sizes of bottles to test the effect of surface area and volume. Appropriate volumes of insulin were combined with insulin I 125 and D5W or NS to yield solutions containing nine concentrations of insulin to test the effect of insulin concentration. Appropriate volumes of KCl injection to yield six concentrations were combined with insulin I 125 and NS or D5W to test the effect of KCl concentration. All samples were assayed by gamma scintillation. In general, there was a direct relationship between the percentage of insulin adhering and the container surface area. In D5W admixtures, as the fill volume at constant insulin I 125 concentration was doubled and quadrupled, the adherence of insulin decreased in all three bottle sizes (200, 250, and 500 ml). In NS admixtures, however, this effect was seen only with the 250-ml bottle. Increasing insulin concentrations over the range of 50-300 units/liter in D5W and 0-50 units/liter in NS resulted in decreased adherence. The addition of 1-60 meq/liter of KCl resulted in a significant decrease of insulin adhering from D5W and an insignificant decrease from NS admixtures. The percentage of insulin adhering to type I glass surfaces may be reduced to 25% or less by preparing i.v. admixtures in full bottles of D5W or NS at insulin concentrations of 25 to 300 units/liter. The addition of KCl, when therapeutically appropriate, will further decrease the extent of insulin adherence.

Adsorption↗

Risk of handling injectable antineoplastic agents.

Uptake of mutagenic substances by persons handling injectable antineoplastic agents was studied, and various methods of preventing such exposure were evaluated. Six persons who prepared i.v. admixtures individually collected their urine in 24-hour batches during several eight-day study periods; each prepared from 12 to 90 admixtures per working day during each period. I.V. personnel prepared admixtures in both horizontal laminar-flow hoods and vertical-flow biological-safety cabinets, and using gloves and masks. Three pharmacy personnel who did not handle any drugs served as controls. Urine was concentrated (each 24-hour sample was concentrated to about 1 ml), and the Salmonella/mammalian microsome mutagenicity test (Ames test) was used to detect mutagenic activity in the urine concentrates. Mutagenicity was observed in the urine of all personnel during periods when they prepared antineoplastic admixtures in horizontal laminar-flow hoods, both when using no protection and while wearing gloves or masks. When admixtures were prepared in the vertical-flow biological safety cabinet by personnel wearing gloves, no urine mutagenicity was detected. The control group showed no urine mutagenicity. Protective intervention methods should be used by all persons handling antineoplastic agents. Guidelines for handling these drugs are presented.

Animals↗

Stability and visual compatibility of bretylium tosylate with selected large-volume parenterals and additives.

The stability of bretylium tosylate when mixed with large-volume parenteral (LVP) solutions was assessed over a four-week period, and the compatibility of bretylium tosylate when mixed with eight frequently used drugs was evaluated. Bretylium tosylate admixtures of approximately 1 mg/ml were prepared in both polyvinyl chloride (PVC) bags and glass bottles of 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection. The admixtures were examined visually and stored for four weeks at 25 +/- 0.5 degree C under fluorescent light. The concentrations of bretylium tosylate were determined spectrophotometrically at times 0.25, 0.5, 1, 3, 8, 24, and 48 hours and twice weekly thereafter for four weeks. Spectrophotometric assays were confirmed with high-pressure liquid chromatography. Admixtures of bretylium tosylate were prepared with aminophylline, calcium gluconate, digoxin, regular insulin, lidocaine hydrochloride, phenytoin sodium, procainamide hydrochloride, and quinidine gluconate in 5% dextrose injection and 0.9% sodium chloride injection. The admixtures were examined visually for 48 hours. The concentration of bretylium tosylate did not change appreciably during the four-week study period. There were no signs of haze, precipitation, color change, or evolution of gas. There were no apparent differences in stability when comparing the glass with the PVC containers. Bretylium tosylate was also found to be compatible with all the additives tested except phenytoin sodium; a precipitate formed immediately when the latter drug was added to the bretylium tosylate solution. Bretylium tosylate was stable for four weeks in the LVP solutions studied in both glass and PVC containers. The admixtures of bretylium sodium with the other drugs were all visually compatible except those containing phenytoin sodium.

Bretylium Compounds↗

Compatibility of mephentermine sulfate with hydrocortisone sodium succinate or aminophylline in 5% dextrose injection.

The compatibility and stability of mephentermine sulfate with hydrocortisone sodium succinate or aminophylline in 5% dextrose injection were studied. Mephentermine sulfate injection (equivalent to mephentermine 300 mg) was added to both hydrocortisone sodium succinate injection (equivalent to hydrocortisone 100 mg--admixture I) and aminophylline injection 250 mg (admixture II), each in 5% dextrose injection 400 ml. The solutions were stored in sealed USP type I containers and stored at 0-4 degrees C, 30 +/- 2 degrees C, and 45 +/- 1 degree C. Aliquots were drawn initially and at 4 and 24 hours for pH, drug content, and degradation product determinations. Mephentermine sulfate content was analyzed by a spectrophotometric method involving ion-pair extraction with tropaeolin 00. Hydrocortisone sodium succinate and aminophylline were analyzed by color reaction with isoniazid and UV spectrophotometry, respectively. The content of mephentermine and total hydrocortisone showed no change in admixture I under all test conditions. Hydrocortisone sodium succinate ester hydrolyzed slowly, but not more than 5% after 24 hours at 45 degrees C. There was no appreciable loss of mephentermine sulfate or aminophylline potency in admixture II. The pH of the solutions did not change over the period of study. The results indicate that both admixtures were compatible and stable under the tested storage conditions for at least 24 hours.

Aminophylline↗

[Spectrophotometric determination of nystatin based on Ashton and Tootill's method].

Estimation of the calculation formula coefficient for quantitative spectrophotometric determination of substances in the presence of a nonlinear absorbing admixture with the method of Ashton and Tutyl is illustrated with reference to nistatin. The procedure is based on representation of the admixture absorption spectrum by the ortogonal polynome of L power. The calculation formulas for the assay of nystatin containing admixtures, the absorption spectra of which may be depicted by the polynomes of the 2nd, 3rd and 4th powers of the wave length were developed with the use of the EI%Icm value of the International standard. The formulas were used for the assay of model mixtures of nistatin with nonidentified admixtures isolated from production samples and having different characters of the absorption spectra. The error of the assay ranged within 0.1-0.5% and increased to 5% only when the admixture had a pronounced absorption maximum in the used spectral region and 1-2. The standard error of an assay performed according to the described procedure with the nystatin content of 1 . 10(-3)% was about 2 . 10(-5)%. This correlated well with preliminary estimation of the assay reproducibility performed with the use of the previously suggested criterion.

Computers↗

[Evaluation of a new intravenous device].

Problems associated with intravenous (IV) admixture preparation include contamination by microorganisms, human error and expense. To solve some of these problems, the Vialink system was developed by Travenol, Israel. This device enables enhanced sterility in clinical settings, since in the preparation of the admixture there is only a single penetration of the rubber seal of the vial. The dilution is performed immediately prior to administration, thereby reducing the possibility of wastage due to unused admixture. In addition, Vialink offers a means of double-checking the contents of the admixtures, since the emptied vial remains attached to the infusion bag. Results of our evaluation of this new system indicate that it offers substantial savings in preparation time and expense. It was suitable for 58.2% of all IV admixtures routinely hospital-prepared. The Vialink system may be a useful strategy, as it improves the quality of the service provided by the health service team and hospital pharmacists to their patients, and results in savings in budget and manpower.

Drug Combinations↗

Doxorubicin/vinblastine and doxorubicin/cyclophosphamide combination chemotherapy by continuous infusion.

Fifty-two patients received one of two doxorubicin (DOX)-based admixtures; DOX plus cyclophosphamide (CTX) or DOX plus vinblastine (VBL) administered as a continuous 24-hour infusion for protracted periods. Compatibility and stability of the two-drug admixture was established for a minimum of 7 days. Twenty patients on the DOX/CTX admixture were infused for a median of 20 days (range, 7-56 days). DOX/VLB was infused in 32 patients for a median of 18 days (range, 5-48 days). Dose limiting toxicity was leukopenia observed in 14/52 patients; 4/20 on DOX/CTX and 10/32 on DOX/VLB. Additional toxicities observed included stomatitis (15%) and subclavian vein thrombosis (23%). Tumor responses were observed in 11 patients, including 6/13 breast cancer; 2/2 hepatoma; 2/4 sarcoma and 1/1 ovarian cancer. Responses were relatively short-lived and no responses were noted in known anthracycline resistant tumors. Admixtures of chemotherapeutic agents represents a novel, but feasible, mechanism for delivery of multiple drugs with an infusion schedule and can be considered for Phase III comparative clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗

Unequal contributions of male and female gene pools from parental populations in the African descendants of the city of Melo, Uruguay.

In admixed populations, genetic contributions from males and females of specific parental populations can be of different proportions due to past directional mating during the process of genetic admixture. In this research paper, we provide evidence of such male- and female-specific differential admixture components of African, European, and American Indian origin in an admixed population from the city of Melo, in the northeastern region of Uruguay. From data on 11 autosomal markers from a sample of 41 individuals of mixed African descent, we estimated 47% African, 38% European, and 15% Amerindian contributions. In contrast, 6 mtDNA site-specific polymorphic markers showed that the mtDNA genome of these individuals was 52% African, 19% European, and 29% Amerindian, while from 3 Y-specific polymorphic sites, we estimated 30% African, 64% European, and 6% Amerindian contributions. We argue that this heterogeneity of admixture estimates results from disproportionate unions of European males with African and American Indian females from which this mixed African population was formed. Also, we argue that the asymmetry of the admixture estimates from the three sets of markers (autosomal, mtDNA, and Y-linked) is a result of the changes in the direction of mating during the history of the population. Implications of such evidence of directional mating are discussed, indicating the need of further demographic data for a quantitative assessment of the impact of directional mating on genetic structure of admixed populations.

Africa↗

Gm and Inv studies on eight Iranian populations with distance measures among the six from the Caspian Littoral.

Serum samples from six populations living in the Caspian Littoral anf from two populations (Armenians and Muslims) living in Teheran were tested for Gm(1,2,3,5,6,10,11,13,14,17,21,24,26) and for Inv(1). The Gm data show that all six populations from the Littoral have African and Mongoloid admixture. Genetic distance among these six populations was estimated using Nei's standard distance measure, and its standard error, based on the 11 loci analyzed by Kirk et al. (1977); on these 11 loci plus Gm; and on the foregoing 12-plus Inv. Only the distance measures for populations 1 and 4, 2 and 3 are significantly different in all three measures of distances, and then only at the 5% level. More loci will have to be studied before firmly based conclusions may be drawn concerning the relation of these populations to each other. The Armenian population, unlike the remaining seven populations, shows no evidence of African admixture, but it does show Mongoloid admixture. The Muslim population shows African and Mongoloid admixture and, in addition, has the unusual haplotype Gm3,5,10,11,14,17,26 at polymorphic frequencies.

Armenia↗

Cost evaluation of a new iv device in an Israeli hospital.

A new device for IV admixtures has been developed in Israel, the Vialink minibag. It consists of a partly filled minibag, attached by rubber tubing to a sterile receptable into which various types of vials containing drugs can be firmly inserted. Time and motion studies were conducted to determine the time and cost associated with the preparation, dispensing and administration of reconstituted parenteral antibiotics via CIVAS (within minibags or Vialink bags) and preparation by nurses in wards in minibags. CIVAS with minibags was least expensive, followed by Vialink minibags. Self preparation on the ward by nurses was found to be the most expensive system. Only 55% of all IV admixtures can be prepared by the Vialink system. As only one hospital in Israel has CIVAS, the study provides a solid justification for implementing pharmacy intravenous admixture services in all Israeli hospitals. The advantages and disadvantages of each method are discussed. CIVAS (minibags and Vialink) permits the individualised preparation of sterile admixtures for each patient and provides advantages in terms of efficiency, economy and prevention of errors.

Costs and Cost Analysis↗