Paul H. Whiting

Effects of ibuprofen on exercise-induced muscle soreness and indices of muscle damage.

Thirty-two volunteers participated in a two-period crossover study in which ibuprofen was tested against an identical placebo for its effectiveness in reducing muscle soreness and damage after two bouts of downhill running. Subjective soreness, quadriceps isometric strength and isometric endurance time at 50 percent of maximum strength, serum activities of creatine kinase, lactate dehydrogenase and aspartate transaminase and serum levels of creatinine and urea were recorded at intervals up to 72 hours after exercise. Each downhill run produced muscle soreness, and a decline in muscle strength and 50 percent endurance time, although these parameters were unaffected by ibuprofen treatment. All serum parameters measured increased after both runs, but for the three enzymes this increase was smaller after the second run. Serum creatine kinase and urea levels were higher in the ibuprofen group after both runs. These results indicate that ibuprofen is not an appropriate treatment for delayed onset muscle soreness and damage.

Toxicity of rapamycin : a comparative and combination study with cyclosporine at immunotherapeutic dosage in the rat

Sprague-Dawley rats were treated for 14 days with rapamycin (RAP; 1.5 mg/kg/day i.p.), cyclosporine (15 mg/kg/day by gavage), both drugs in combination, or appropriate drug vehicles. Hematological parameters and biochemical indices of renal and hepatic function were determined throughout the experimental period, at the end of which the rats were killed and tissues examined histologically. There was a significant reduction in weight gain in RAP- but not CsA-treated animals, while rats given both drugs showed a reduction in body weight over the 14-day experimental period. There were no significant alterations in absolute or differential white blood cell counts or in T or B cell numbers, except in the drug combination group, in which an absolute lymphopenia was detected on day 14. Small but significant increases in urinary flow rate (UFR) were found with either drug alone, and there was a marked (4-fold) increase in UFR in response to drug combination. Both RAP and CsA caused a small elevation in serum creatinine concentrations, but only with CsA was there a significant elevation in urinary enzyme activity and reduction in 51Cr. EDTA clearance. The drug combination exacerbated renal impairment, the extent of which was greater than the additive effect of either drug alone. Hyperbilirubinemia of similar magnitude was observed in rats receiving either CsA alone or in combination with RAP. In contrast to its effect on renal function, however, the CsA+RAP combination was without additional effect on liver function compared with the minor changes seen with either drug alone. Plasma and urinary glucose levels were elevated in all drug treatment groups and especially in animals given both drugs. RAP administration did not significantly affect whole-blood CsA concentrations, although the possibility of a pharmacokinetic interaction cannot be totally excluded. Histological studies revealed striking thymic medullary atrophy in all drug-treated animals. In addition, all rats given RAP showed focal myocardial necrosis of overall mild-moderate severity. Kidneys of RAP-treated rats appeared normal, whereas mild, focal, acute tubular necrosis was evident in all CsA-treated animals. Pancreases of all drug-treated animals were normal.

Cyclosporine: immunology, toxicity and pharmacology in experimental animals.

Cyclosporine (CsA) is the first of a new order of pharmacological immune suppressants and represents a significant advance in the clinical control of graft rejection. In laboratory animals, its capacity to prolong allograft survival has been well documented, including reports of indefinite donor-specific immunological tolerance after shortterm CsA treatment. There is also evidence that CsA can inhibit the onset or progress of a variety of experimental autoimmune diseases. Underlying these properties of the drug is its capacity to selectively interfere with T helper cell activation and lymphokine production, although some direct effects on B cells have also been reported. In addition, sparing of suppressor cells may in part explain the mode of action of CsA which, at the molecular level, is not understood.CsA-induced nephrotoxicity in the rat has been extensively studied and is characterized by reversible proximal tubular cell damage. This problem may be aggravated by concomitant administration of other potentially nephrotoxic drugs, such as gentamicin, or by therapeutic agents which interfere with the metabolism of CsA.CsA is metabolized in the liver and excreted in the bile. Although the pathway of hepatic metabolism of CsA has not been precisely elucidated, animal studies suggest that agents capable of inducing metabolism of the drug CsA could be used to alleviate its nephrotoxic properties.

Serum and urine N-acetyl-beta-D-glucosaminidase in diabetics on diagnosis and subsequent treatment, and stable insulin dependent diabetics.

N-Acetyl-beta-D-glucosaminidase (NAG) activity has been measured in the serum and urine of diabetics. Results have shown significantly higher levels of serum NAG in newly diagnosed diabetics (945 +/- 372 units/ml) compared to non-diabetic controll (668 +/- 225, p less than 0.005) and the levels were reduced by treatment (778 +/- 218, p less than 0.05). Changes occurred in the same direction when urinary NAG was measured falling from a mean of 572 +/- 298 units/mg urinary creatinine, on diagnosis to 291 +/- 176 after treatment (p less than 0.005), as compared with 177 +/- 86 in non-diabetic controls. Established insulin-treated diabetics had a urinary NAG activity of 461 +/- 440 and a serum NAG activity of 790 +/- 245. No correlation was found between urine NAG activity and urine glucose (r = 0.315), or serum NAG and serum glucose (r = 0.273). An assessment of this enzyme is made in relation to early microangiopathy.

Effects of a non-steroidal anti-inflammatory drug on delayed onset muscle soreness and indices of damage.

Twenty untrained male volunteers were required to run downhill for 45 minutes on a motor driven treadmill to induce muscle soreness. The volunteers took diclofenac or placebo before and for 72 hours after two runs 10 weeks apart, in a randomised double blind crossover design. Subjective soreness was assessed before and at intervals up to 72 hours after each run; venous blood samples, collected at the same time intervals, were used to estimate serum activities of creatine kinase, lactate dehydrogenase and aspartate aminotransferase and serum concentrations of creatinine and urea. Subjective soreness and the biochemical parameters increased after both runs, although the serum enzyme response to the second run was reduced. Diclofenac had no influence on the serum biochemical response to downhill running. Although overall soreness was not affected by diclofenac, individual soreness measurements were reduced by diclofenac at the first period of the study. These results suggest that diclofenac does not influence muscle damage, but may slightly reduce the associated soreness.

Estimation of plasma volume changes during marathon running.

Indices of fluid loss have been compared in 47 male runners who completed a competitive marathon (42.2 km) race in times varying from 2 hr 37 min to 4 hr 51 min. Body weight was recorded before and after the race; venous blood samples were collected shortly before and immediately after the race and used for the estimation of haemoglobin concentration, packed cell volume and serum concentration of albumin and total protein. All runners drank a total of 1.4 L of water during the race. The mean decrease in body weight was 2.1 +/- 0.8 kg (mean +/- SD), corresponding to 3.0 +/- 1.1% of initial weight. The decrease in plasma volume (PV), calculated from the haematological parameters, was 6.5 +/- 7.8% (P less than 0.001). Serum total protein concentration increased (P less than 0.001) by 10.4 +/- 4.8% and serum albumin (P less than 0.001) by 9.6 +/- 5.6%. The increase in serum protein concentration was correlated (r = 0.64, P less than 0.001) with the calculated decrease in PV, but was greater (P less than 0.001) than could be accounted for by the loss of plasma water. The change in PV varied widely between individuals and was unrelated to running speed. The estimated decrease in total body water (5%) was not different from the decrease in PV (6.5%), suggesting that water losses were evenly distributed between the intracellular and extracellular compartments.

A toxicological study in rats receiving immunotherapeutic doses of cyclosporin A.

SUMMARY Cyclosporin A (Cy A, 25 or 50 mg.kg-1/48 hr) administered during the course of the response, markedly suppressed graft-versus-host (GVH) reactivity in the rat, as assessed by the 7-day popliteal lymph node weight assay. Serum biochemical studies revealed small, but statistically significant increases in serum urea levels at both doses of Cy A and, at 50 mg.kg-1/48 hr, reduction in total serum protein, alkaline phosphatase, serum transaminase, and iron. In an additional experiment, Cy A (50 mg.kg-1/48 hr) was administered to rats over 4 weeks. Serum biochemical and hematological investigations were conducted at weekly intervals and at 28 days tissue (liver, kidney, spleen, lymph nodes, and small intestine) was taken for histological and ultrastructural examination. Glomerular function, monitored by creatinine and urea clearance was unaffected by Cy A treatment, but serum urea and creatinine levels were elevated. Hepatic function was not affected and hematological, histological, and ultrastructural observations, apart from evidence of hepatic fatty change, did not differ from those in vehicle-treated controls.

N-acetyl-β-d-glucosaminidase levels and diabetic microangiopathy

N-Acetyl-beta-D-glucosaminidase (NAG) activity has been measured in the serum and urine of primary and secondary diabetics and in primary diabetics with microangiopathy. NAG activity has also been measured in the tears of diabetics with ocular complications and diabetics with no ocular changes. Results have shown significantly higher levels of urinary NAG in diabetics with proteinuria (p less than 0.001) and proteinuria and retinopathy (p less than 0.001). There was no correlation between urinary NAG activity and serum creatinine (r = 0.28) or urinary NAG and the degree of proteinuria (r = 0.24). Increased urinary NAG levels were also observed in secondary diabetes associated with haemochromatosis and acromegaly. Significantly higher serum NAG levels were found in newly diagnosed diabetics (p less than 0.01) and significantly lower levels in chemical diabetics (p less than 0.01). Compared to non-diabetic controls tear NAG levels were significantly higher in the diabetic controls (p less than 0.01), in diabetics with retinopathy (p less than 0.01), and in diabetics with cataract formation (p less than 0.05). An assessment of this enzyme is made in relation to the development of diabetic microangiopathy.

Patterns of N-acetyl-β-d-glucosaminidase excretion after renal transplantation

N-Acetyl-beta-D-glucosaminidase activity (NAG) was assayed in 750 early morning urine samples from 25 renal transplant patients during the post operative period. Eighty four per cent of all acute rejection episodes were preceded or accompanied by a greater than two-fold rise in NAG activity; similar increases were caused by dialysis, gentamicin therapy and ureteric dehiscence. Only 9% of all significant increases in NAG excretion could not be accounted for by any of these four processes. Analysis of the day-to-day pattern of NAG activity as opposed to individual NAG values provided a clue to the occurrence of rejection during immediate post-transplantation oliguria.

Amelioration of cyclosporin-induced nephrotoxicity in rats by induction of hepatic drug metabolism

The aim of this study was to determine the effect of altered hepatic drug metabolism on the nephrotoxic and immunosuppressive properties of cyclosporin A (CsA) in the rat. From a consideration of the structures of those CsA metabolites identified so far, it seemed probable that the metabolism of CsA would occur at the hepatic cytochrome P-450 (cyt P-450) enzyme system. CsA (50 mg/kg/24 hr) administered orally for 14 days resulted in significant increases in both serum urea concentration and urinary N-acetyl-beta-D-glucosaminidase activity, accompanied by renal proximal tubular vacuolation. The concomitant administration of either Aroclor 1254 (25 mg/kg/24 hr, i.p.) or phenobarbitone (PB) (40 mg/kg/24 hr, i.p.) but not 3-methylcholanthrene (3-MC) (15 mg/kg/72 hr, i.p.) resulted in abolition of the nephrotoxicity, assessed both biochemically and histologically, whilst the suppressive effect on the humoral response to SRBC was unaltered. Phenobarbitone also significantly decreased serum CsA concentrations. These results suggest that the PB-inducible set of cyt P-450 isoenzymes may be responsible or partly responsible for hepatic CsA metabolism.