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    Mean ± SEM values for GFR in 12 female Beagles that received a placebo (white circles), furosemide alone (white squares), etodolac and furosemide (black squares), and carprofen and furosemide (black triangles). The GFR was determined immediately before drug administration (day 1), immediately after 8 days of drug administration (day 8), and 12 days after the end of drug administration (day 20). Within each treatment, values are expressed as a percentage of day 1 values. *Value is significantly (P < 0.05) different from the value for the placebo treatment. †Value is significantly (P < 0.05) different from the value for administration of furosemide alone.

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    Surdyk KKSloan DLBrown SA. Evaluation of the renal effects of ibuprofen and carprofen in euvolemic and volume-depleted dogs. Intern J Appl Res Vet Med 2011; 9:129136.

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Renal effects of carprofen and etodolac in euvolemic and volume-depleted dogs

Kathryn K. Surdyk DVM, PhD1, Dawn L. Sloan BS2, and Scott A. Brown VMD, PhD3
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  • 1 Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
  • | 2 Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
  • | 3 Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Abstract

Objective—To determine the effects of carprofen and etodolac on renal function in euvolemic dogs and dogs with extracellular fluid volume depletion induced via administration of furosemide.

Animals—12 female Beagles.

Procedures—Dogs received a placebo, furosemide, carprofen, etodolac, furosemide and carprofen, and furosemide and etodolac. The order in which dogs received treatments was determined via a randomization procedure. Values of urine specific gravity, various plasma biochemical variables, glomerular filtration rate (GFR [urinary clearance of creatinine]), and renal plasma flow (urinary clearance of para-aminohippuric acid) were determined before and after 8 days of drug administration. A washout time of approximately 12 days was allowed between treatment periods.

Results—Administration of furosemide, furosemide and carprofen, and furosemide and etodolac caused changes in urine specific gravity and values of plasma biochemical variables. Administration of carprofen or etodolac alone did not have a significant effect on renal plasma flow or GFR. Concurrent administration of furosemide and carprofen or furosemide and etodolac caused a significant decrease in GFR. After 12-day washout periods, mean values of GFR were similar to values before drug administration for all treatments.

Conclusions and Clinical Relevance—Results indicated GFR decreased after 8 days of concurrent administration of furosemide and carprofen or furosemide and etodolac to dogs. Administration of preferential cyclooxygenase-2 inhibitors to dogs with extracellular fluid volume depletion or to dogs treated with diuretics may transiently impair renal function.

Abstract

Objective—To determine the effects of carprofen and etodolac on renal function in euvolemic dogs and dogs with extracellular fluid volume depletion induced via administration of furosemide.

Animals—12 female Beagles.

Procedures—Dogs received a placebo, furosemide, carprofen, etodolac, furosemide and carprofen, and furosemide and etodolac. The order in which dogs received treatments was determined via a randomization procedure. Values of urine specific gravity, various plasma biochemical variables, glomerular filtration rate (GFR [urinary clearance of creatinine]), and renal plasma flow (urinary clearance of para-aminohippuric acid) were determined before and after 8 days of drug administration. A washout time of approximately 12 days was allowed between treatment periods.

Results—Administration of furosemide, furosemide and carprofen, and furosemide and etodolac caused changes in urine specific gravity and values of plasma biochemical variables. Administration of carprofen or etodolac alone did not have a significant effect on renal plasma flow or GFR. Concurrent administration of furosemide and carprofen or furosemide and etodolac caused a significant decrease in GFR. After 12-day washout periods, mean values of GFR were similar to values before drug administration for all treatments.

Conclusions and Clinical Relevance—Results indicated GFR decreased after 8 days of concurrent administration of furosemide and carprofen or furosemide and etodolac to dogs. Administration of preferential cyclooxygenase-2 inhibitors to dogs with extracellular fluid volume depletion or to dogs treated with diuretics may transiently impair renal function.

Administration of NSAIDs to dogs can cause toxic effects in the gastrointestinal tract and kidneys.1–3 Toxic effects in the gastrointestinal tract may be reduced via administration of NSAIDs that preferentially inhibit COX-2.4 To the author's knowledge, the effects of such drugs on renal function in dogs (particularly dogs with disease) are not known. The finding of other authors1–3 that toxic effects in the gastrointestinal tract and kidneys develop after administration of NSAIDs to animals may be attributable to synergism among factors responsible for these effects. In particular, vomiting associated with NSAID-induced toxic effects in the gastrointestinal tract can cause volume depletion and metabolic alkalosis, which might increase toxic effects of such drugs in the kidneys.

Because COX-1 may have important effects for maintenance of GFR and RPF, a drug that preferentially inhibits COX-2 (ie, selective COX-2 inhibitor) may have less impact on kidney function versus an NSAID that nonselectively inhibits both COX isoenzymes (ie, nonselective COX inhibitor). However, in another study5 conducted by our research group that included dogs with furosemide-induced volume depletion and metabolic alkalosis, administration of a nonselective COX inhibitor (ibuprofen) and a selective COX-2 inhibitor (carprofen) to dogs caused similar, significant decreases in GFR.

Carprofen and etodolac are NSAIDs that may be prescribed for the treatment of acute and chronic pain in dogs. Analgesic effects of these drugs are mediated via inhibition of prostaglandin synthesis.6–8 The propionic acid derivative, carprofen, has 5- to 6-fold selectivity for the inhibition of COX-2,9 and this drug is typically classified as a preferential inhibitor of COX-2.10,11 Etodolac is COX-2 selective in humans and rats.12,13 It has been reported14 that etodolac is COX-1 selective in dogs, although results of other studies4,15 indicate etodolac is a preferential COX-2 inhibitor in dogs and that it is less selective for the inhibition of COX-2 than is carprofen.16 However, the effects of NSAIDs and their relative selectivities for COX isoenzymes may be tissue specific. Because etodolac may be a more effective inhibitor of COX-1 in the renal vascular bed than is carprofen, etodolac may have greater adverse effects on renal hemodynamics.

The purpose of the study reported here was to determine the effects of carprofen and etodolac on renal hemodynamics in dogs. Our hypothesis was that carprofen would have a smaller effect on renal hemodynamics than would etodolac in dogs with extracellular fluid volume depletion induced by administration of furosemide.

Materials and Methods

Animals—Twelve female Beagles (age range, 8 months to 2 years; mean ± SD body weight, 9.4 ± 0.3 kg) owned by the University of Georgia were used in the study. For each dog, results of physical examination, a CBC, and serum biochemical analyses were unremarkable. Each dog was housed separately in an indoor, temperature-controlled environment; fed 125 kcal/kg0.75 of a maintenance feed17,a formulated for dogs (which contained 26% protein, 16% fat, 3% fiber, 12% moisture, 1.3% salt, 1.0% calcium, and 0.8% phosphorus on a dry-matter basis) once daily; and allowed free access to water. Dogs were observed at least twice daily by a veterinarian (KKS or SAB) or a veterinary technician (DLS) to detect clinical abnormalities. Daily food intake was measured as the difference between the weight of the amount of food provided at feeding time and the weight of food remaining when a dog was fed again. Three weeks prior to the start of the present study, these dogs had been used in another study.5 The present study was conducted in compliance with the Animal Welfare Act, the US Public Health Service Policy on the Humane Care and Use of Laboratory Animals, and the National Research Council Guide for the Care and Use of Laboratory Animals. The study was approved by the University of Georgia Animal Care and Use Committee.

Experimental design—Six treatments (A = placebo,b B = carprofen,c C = etodolac,d D = furosemide,e E = carprofen and furosemide, or F = etodolac and furosemide), 6 treatment periods (approx 20 days each), and 6 treatment pairs of dogs were included in the present study. A 6 × 6 Latin square crossover design was used to control for treatment order. The order in which treatments were administered to each treatment pair of dogs was predetermined (first pair of dogs: ABCDEF; second pair: BFDCAE; third pair: CDEFBA; fourth pair: DAFECB; fifth pair: ECABFD; and sixth pair: FEBADC). The University of Georgia Animal Care and Use Committee assigned each dog a unique number that was used for identification. These identification numbers were used to assign each dog to a treatment pair. The order of these identification numbers was determined by use of a randomization procedure with statistical software.f This order was used to sequentially assign the dogs to the first through sixth treatment pairs. Thus, the dogs with the first 2 identification numbers in the randomized order of numbers were assigned to the first treatment pair, the dogs with the third and fourth identification numbers in the random order were assigned to the second treatment pair, and so on. Drugs or placebo treatments were administered to dogs during the first 8 days of each treatment period, which was followed by a drug withdrawal period of 10 to 13 days before each pair of dogs received the next treatment. Day 1 of each treatment period was defined as the day on which a dog first received a treatment.

Between 7:00 am and 12:20 pm on day 1 of each treatment period, renal clearance for each dog was determined. Starting between 2:00 pm and 5:00 pm on day 1, treatments were administered to dogs. Drug dosages were determined on the basis of body weight of each dog (determined on day 1 of each treatment period). The intended dosages were 2.2 mg/kg, PO, twice daily for carprofen18; 12.5 mg/kg, PO, once daily for etodolac18; and 4 mg/kg, PO, twice daily for furosemide. The carprofen and etodolac dosages were selected on the basis of those recommended in package inserts for each drug.18 The actual dosages varied slightly from intended dosages because of limitations attributable to available drug tablet sizes. The last dose of each drug was administered at 7:00 am on day 8 of each treatment period. Renal clearance was determined beginning 75 to 90 minutes after administration of drugs on day 8. Medication was discontinued for 10 to 13 days, at which time the next treatment period was started.

Renal clearance—Beginning 3 months prior to the start of the study, dogs were acclimated to urine collection stands during a 2-hour period once per week. Before determination of renal clearance, food was withheld from dogs for 12 to 20 hours; dogs were allowed ad libitum access to water during that period. Glomerular filtration rate and RPF were assessed for each dog via determination of urinary clearance of creatinine and PAH,g respectively. For determination of GFR and RPF, urinary catheters were aseptically placed in dogs. Dogs received water equal to 3% of body weight (wt/vol) via gavage. Immediately after dogs received water, a solution containing 25 mg of creatinine and 3.75 mg of PAH/mL was administered (2 mL/kg) SC to each dog. Dogs received a second injection of the creatinine and PAH solution (0.6 mL/kg, SC) 25 minutes later. The bladder of each dog was emptied and lavaged with sterile distilled water. Urine was collected from each dog during 3 consecutive 30-minute periods, starting approximately 50 minutes after dogs received the first dose of creatinine and PAH. A venous blood sample (2 mL) was obtained from a jugular vein of each dog at the beginning of each urine collection period and at the end of the third urine collection period; blood samples were collected into tubes containing heparin (final concentration, approx 5 U of heparin/mL of blood).

Plasma and urine analyses and determination of GFR and RPF—Plasma concentrations of BUN, creatinine, and electrolytes were determined by use of an automated analyzer.h Creatinine concentrations in plasma and urine were measured with an automated analyzer, and PAH concentrations in urine were measured via a standard chemical method.19 Urine specific gravity was determined with a refractometer.i Urinary clearance of creatinine and PAH was calculated by use of a standard clearance formula,19 and values were used as measures of GFR and RPF, respectively. Filtration fraction was determined with the following formula: filtration fraction = GFR/RPF.

Statistical analysis—Statistical analyses were performed with commercially available software.f Normal distribution of data was verified with the Shapiro-Wilk test, and data were compared among treatments via repeated-measures ANOVA. Data were reported as mean ± SEM. Values of P < 0.05 were considered significant.

Results

Drug dosages—The mean ± SEM dosage of furosemide administered to dogs was 3.8 ± 0.1 mg/kg, PO, twice daily and was not significantly different among treatments (furosemide, carprofen and furosemide, and etodolac and furosemide) or treatment periods. The mean ± SEM dosage of carprofen administered to dogs was 2.3 ± 0.1 mg/kg, PO, once daily and was not significantly different between treatments (carprofen alone and the combination of carprofen and furosemide). The mean ± SEM dosage of etodolac administered to dogs was 13.6 ± 0.2 mg/kg, PO, once daily and was not significantly different between treatments (etodolac alone and the combination of etodolac and furosemide). No adverse effects of drug administration or changes in food intake were detected during the study.

Values of variables before drug administration—Significant differences were not detected among mean day 1 values for body weight, RPF, GFR, or plasma concentrations of electrolytes, BUN, or creatinine. There was no significant treatment effect on mean daily food intake by dogs.

Effects of furosemide—Urine specific gravity and plasma concentrations of chloride and potassium were significantly lower and BUN and plasma bicarbonate concentrations were significantly higher in samples obtained from dogs on day 8 of furosemide administration versus those in samples obtained from dogs on day 8 of placebo administration (Table 1). Values of GFR and RPF for dogs on day 8 of furosemide administration were not significantly different from values for dogs on day 8 of placebo administration (Table 2; Figure 1).

Table 1—

Results of urine specific gravity and plasma biochemical analyses for 12 female Beagles on days 1 and 8 of various treatment protocols.

Time and treatmentCreatinine (mg/dL)BUN (mg/dL)Na+ (mmol/L)Cl (mmol/L)K+ (mmol/L)HCO3- (mmol/L)Urine specific gravity
Day 1
   None0.92 ± 0.0213.0 ± 0.3147 ± 1111 ± 14.3 ± 0.120.8 ± 0.21.028 ± 0.002
Day 8
   Placebo0.93 ± 0.03a13.1 ± 0.5a147 ± 1a111 ± 1a4.2 ± 0.1a21.4 ± 0.5a1.029 ± 0.004a
   Carprofen1.01 ± 0.06a,b15.2 ± 1.4a,147 ± 1a111 ± 1 a4.2 ± 0.1a22.3 ± 0.9a1.031 ± 0.004a
   Etodolac0.93 ± 0.03a14.9 ± 1.2147 ± 1a112 ± 1 a4.2 ± 0.1a21.4 ± 0.6a1.032 ± 0.003a
   Furosemide1.03 ± 0.06a,b17.3 ± 0.8b,c146 ± 1a104 ± 1b3.7 ± 0.1b23.6 ± 0.6b1.006 ± 0.001b
   Carprofen and furosemide1.09 ± 0.04b17.9 ± 0.8b,c148 ± 1a106 ± 1b3.7 ± 0.1b23.5 ± 0.5b1.008 ± 0.001b
   Etodolac and furosemide1.13 ± 0.09b19.5 ± 1.6c144 ± 1 a103 ± 1b3.6 ± 0.1b24.3 ± 0.6b1.011 ± 0.003b

Values are mean ± SEM.

Within a column, day 8 values with no shared superscript letters are significantly (P < 0.05) different.

Table 2—

Results of renal clearance analyses for the dogs in Table 1 on days 1 and 8 of various treatment protocols.

TreatmentGFR (mL/min/kg)RPF(mL/min/kg)Filtration fraction
Day 1Day 8Day 1Day 8Day 1Day 8
Placebo3.24 ± 0.10a3.16 ± 0.10a13.8 ± 1.0a13.7 ± 0.7a0.25 ± 0.02a0.23 ± 0.01a,b
Carprofen3.22 ± 0.13a3.29 ± 0.14a14.6 ± 0.9a12.9 ± 0.5a0.24 ± 0.01a0.25 ± 0.01a
Etodolac3.15 ± 0.10a3.19 ± 0.06a13.5 ± 0.6a13.0 ± 0.4a0.24 ± 0.01a0.24 ± 0.01a,b
Furosemide3.23 ± 0.13a3.00 ± 0.10a,c13.7 ± 0.8a13.3 ± 0.9a0.25 ± 0.02a0.23 ± 0.02a,b
Carprofen and furosemide3.21 ± 0.13a2.65 ± 0.08b13.3 ± 1.0a11.7 ± 1.2a0.25 ± 0.01a0.23 ± 0.01b
Etodolac and furosemide3.33 ± 0.13a2.82 ± 0.18b,c14.6 ± 0.9a13.5 ± 1.5a0.23 ± 0.01a0.21 ± 0.02b

Filtration fraction was determined with the following formula: filtration fraction = GFR/RPF.

Within a column, values with no shared superscript letters are significantly (P < 0.05) different.

See Table 1 for reminder of key.

Figure 1—
Figure 1—

Mean ± SEM values for GFR in 12 female Beagles that received a placebo (white circles), furosemide alone (white squares), etodolac and furosemide (black squares), and carprofen and furosemide (black triangles). The GFR was determined immediately before drug administration (day 1), immediately after 8 days of drug administration (day 8), and 12 days after the end of drug administration (day 20). Within each treatment, values are expressed as a percentage of day 1 values. *Value is significantly (P < 0.05) different from the value for the placebo treatment. †Value is significantly (P < 0.05) different from the value for administration of furosemide alone.

Citation: American Journal of Veterinary Research 73, 9; 10.2460/ajvr.73.9.1485

Effects of carprofen—No significant differences were detected between values of any variable on day 8 of carprofen administration and values on day 8 of placebo administration (Tables 1 and 2). Urine specific gravity and plasma concentrations of chloride and potassium were significantly lower in samples obtained from dogs on day 8 of concurrent carprofen and furosemide administration versus those in samples obtained from dogs on day 8 of placebo administration. Blood urea nitrogen and plasma bicarbonate concentrations were significantly higher in samples obtained from dogs on day 8 of concurrent carprofen and furosemide administration versus those in samples obtained from dogs on day 8 of placebo administration. Urine specific gravity and values of plasma biochemical variables on day 8 of concurrent carprofen and furosemide administration were not significantly different from those on day 8 of administration of furosemide alone. The GFR value for dogs on day 8 of concurrent carprofen and furosemide administration was significantly lower than values for dogs on day 8 of administration of placebo, carprofen alone, etodolac alone, or furosemide alone (Figure 1). The day 8 RPF values were not significantly different among treatments.

Effects of etodolac—No significant differences were detected between values of any variable on day 8 of etodolac administration and values on day 8 of placebo administration (Tables 1 and 2). Urine specific gravity and plasma concentrations of chloride and potassium were significantly lower and BUN and plasma bicarbonate concentration were significantly higher in samples obtained from dogs on day 8 of concurrent etodolac and furosemide administration versus values in samples obtained from dogs on day 8 of placebo administration. No significant differences were detected between values of any variable on day 8 of concurrent etodolac and furosemide administration and values on day 8 of administration of furosemide alone. The GFR value for dogs on day 8 of concurrent etodolac and furosemide administration was significantly lower than values on day 8 of administration of placebo, carprofen alone, or etodolac alone and was not significantly different from values for dogs on day 8 of administration of furosemide alone (Figure 1). The day 8 RPF values were not significantly different among treatments.

Discussion

Prostaglandins have various effects in kidneys, including hemodynamic, hemostatic, and cytoprotective effects.7,11,20,21 Prostaglandins also regulate function of the renin-angiotensin-aldosterone system by promoting the release of renin from kidneys in response to extracellular fluid volume depletion.7,20,21 Prostaglandins alter renal tubular processing of water and electrolytes in animals.21

The clinical approach to managing pain in dogs has changed since COX inhibitors with selectivity for COX-2 have become available; such drugs are potentially safer than drugs that are not selective for COX-2. Administration of COX-2–selective drugs is less likely to cause toxic effects in the gastrointestinal tract than administration of drugs that are not selective for COX-2.4 However, the effects of recently developed COX-2–selective NSAIDs in kidneys of dogs are not completely known. Cyclooxygenase isoenzyme-1 is constitutively expressed in kidneys of dogs in collecting duct cells, medullary interstitial cells, endothelial cells, and smooth muscle cells of pre- and postglomerular blood vessels. Cyclooxygenase isoenzyme-1 has a role in the regulation of renal hemodynamics22–24 by enhancing the release of vasodilatory prostaglandins, which maintain RPF and GFR during conditions that would otherwise cause renal vasoconstriction and decreased renal function. Renal expression of COX-2 was previously thought to be inducible and upregulated only during inflammation. However, COX-2 is constitutively expressed in cells of the macula densa, cortical thick ascending limb of the loop of Henle, and medullary interstitium in kidneys of dogs,21,25–29 and results of another study5 conducted by our research group indicate that effects of a preferential COX-2 inhibitor (carprofen) were similar to those of a nonselective COX inhibitor (ibuprofen). To the authors' knowledge, effects of those drugs in the kidneys of dogs had not been compared. Results of our other study5 did not indicate whether the preferential COX-2 inhibitory drug carprofen had unique effects on renal function or whether those effects were typical of all preferential COX-2 inhibitory drugs. Thus, in the present study, we chose to compare the renal effects of carprofen with those of another drug (etodolac), which is thought to be a preferential COX-2 inhibitor4,15 with lower selectivity for COX-2 than for carprofen.16 However, this classification of etodolac is controversial because other investigators14 have determined that etodolac is COX-1 selective.14

In the present study, administration of furosemide to dogs caused an expected decrease in urine specific gravity and alterations in plasma concentrations of chloride, potassium, and bicarbonate. In another study,5 we determined that the same dosage of furosemide as that administered to dogs of the present study causes a reduction (approx 13%) in extracellular fluid volume with accompanying alterations in plasma electrolyte concentrations. These effects of furosemide were consistent with volume-depletion alkalosis. Volume-depletion alkalosis can be induced via administration of diuretics (as in the present study) or severe vomiting, which could be associated with toxic effects in the gastrointestinal tract attributable to administration of NSAIDs. Water (3% of body weight [wt/vol]) was administered to dogs via gavage prior to determination of renal clearance in the present study, which made it impossible to determine the amount by which plasma volume had been reduced at the time of GFR measurement in dogs that received furosemide. However, all dogs received water via gavage and GFR was reduced in dogs on day 8 of carprofen and furosemide administration, compared with that on day 1 (mean reduction, 17.4%); this reduction in GFR was comparable with that detected when dogs received etodolac and furosemide (15.3%). These reductions of GFR may have been attributable to volume depletion or changes in electrolyte concentrations and were considered mild (because they did not result in azotemia or illness).

Carprofen, etodolac, and furosemide, when administered alone, did not have a significant effect on GFR or RPF in dogs of the present study. However, it was expected that furosemide administration would induce a prostaglandin-dependent state in kidneys of the dogs, and concurrent administration of furosemide and either NSAID (carprofen or etodolac) caused a reduction in GFR but not RPF. The finding of a decrease in GFR without a corresponding decrease in RPF indicated that dogs receiving an NSAID and furosemide had preglomerular vasoconstriction and a comparable decrease in postglomerular vascular resistance. In the present study, only administration of carprofen in combination with furosemide caused a significant decrease in GFR, compared with that in dogs receiving furosemide alone. Although this result could indicate a renal-sparing effect of etodolac, the mean GFR values for dogs receiving furosemide and either NSAID (carprofen or etodolac) were not significantly different.

Although adverse effects of drugs were not observed in dogs of the present study and changes in GFR were reversible, reductions in GFR were associated with increases in BUN and plasma creatinine concentrations in these young, healthy dogs that had clinically normal renal function prior to performance of the study. Results of the present study indicated that carprofen and etodolac should be used in a judicious manner in dogs because the effects of these NSAIDs cannot be predicted for dogs with volume depletion attributable to clinical abnormalities.

Results of the present study did not support our hypothesis that the renal effects of carprofen and etodolac would differ in volume-depleted dogs. Findings of the present study and those of our other study5 did not indicate that the renal hemodynamic effects of NSAIDs with different COX selectivities are markedly different. In volume-depleted dogs, the risk for renal complications attributable to administration of COX-nonselective and COX-2–preferential NSAIDs seemed to be similar.

ABBREVIATIONS

COX

Cyclooxygenase

GFR

Glomerular filtration rate

PAH

Para-aminohippuric acid

RPF

Renal plasma flow

a.

Purina ProPlan Chicken and Rice diet, Nestlé Purina PetCare Co, St Louis, Mo.

b.

Gelatin capsules, Eli Lilly & Co, Indianapolis, Ind.

c.

Rimadyl, Pfizer Animal Health, Exton, Pa.

d.

EtoGesic, Fort Dodge Animal Health, Fort Dodge, Iowa.

e.

Salix, Intervet Inc, Millsboro, Del.

f.

Statview, version 4.5, Abacus Concepts Inc, Berkeley Calif.

g.

Sigma Chemical Co, St Louis, Mo.

h.

Abbott Diagnostics, Irving, Tex.

i.

SPR-T2 Refractometer, Atago Co Ltd, Tokyo, Japan.

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Contributor Notes

Address correspondence to Dr. Brown (SBrown01@uga.edu).