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P H Whiting

Publications and source records attributed to P H Whiting.

At least 19 recordsLinked to original sources
PubMed1995

Acute phase proteins and recombinant IL-2 therapy: prediction of response and survival in patients with colorectal cancer.

Twenty-four patients with metastatic colorectal cancer were treated with recombinant IL-2 (rIL-2) by continuous intravenous infusion for 5 days (18 x 10(6) U/m2 per 24 h), followed by three injections of 5-fluorouracil (600 mg/m2) and folinic acid (25 mg/m2) at weekly intervals. The response to treatment was assessed using standard UICC criteria (partial or complete response, stasis or progression of disease). The serum concentrations of the acute phase proteins; C-reactive protein (CRP), retinol binding protein (RBP), alpha 1-antitrypsin (alpha 1-AT), transferrin (TF) and albumin were measured. A response to therapy occurred in the tumours of seven (29%) of the 24 patients (two complete and five partial responses). All patients who demonstrated a response to treatment had a serum albumin level of > 37 g/l and a CRP level of < or = 10 mg/l. In contrast, of the 17 patients who did not respond to therapy, 12 (71%) had a serum albumin of less than 37 g/dl and a CRP of greater than 10 mg/l. Examination of the survival times of the 12 patients who had a pretreatment serum albumin level of less than 37 g/l revealed that all had died within 12 months of cessation of therapy. However, 58% of patients with pretreatment serum albumin levels of greater than 37 g/l survived for longer than 12 months. These results have shown that (i) patients who respond to rIL-2-based therapy and (ii) those patients who have prolonged survival times, can be identified by pretreatment measurement of serum levels of acute phase proteins.

Acute-Phase Proteins↗
PubMed1994

Renal impairment associated with the pre-operative administration of recombinant interleukin-2.

1. The T-cell-derived cytokine interleukin-2 may be used to reverse the immune suppression associated with major surgery. However, both major surgical procedures and recombinant interleukin-2 therapy are known to induce renal dysfunction. 2. Eighteen patients were randomized to receive either recombinant interleukin-2 (18 x 10(6) i.u./day) or placebo, given subcutaneously for 3 days before undergoing curative colorectal cancer surgery. Indices of renal function were determined pre-operatively and for 21 days after surgery. 3. Pre-operative recombinant interleukin-2 was found to significantly increase, compared with placebo controls, N-acetyl-beta-D-glucosaminidase [peak levels 28 (SEM 2) versus 11 (SEM 3) i.u./mmol of Cr] and gamma-glutamyltransferase [peak levels 5.3 (SEM 0.6) versus 2.4 (SEM 0.2) i.u./mmol/l] and decrease urinary fractional excretion of sodium [peak difference 0.32 (SEM 0.06) versus 0.76 (SEM 0.08)] (all P < 0.05). Significantly increased urinary excretions of creatinine, N-acetyl-beta-D-glucosaminidase and gamma-glutamyltransferase were also identified after surgery. All variables returned to pretreatment limits by the seventh day post-operatively, except N-acetyl-beta-D-glucosaminidase, which was still significantly elevated 21 days after surgery. No differences in the serum concentrations of sodium, creatinine or urea were observed before or after surgery in either group. 4. Recombinant interleukin-2, when given in the preoperative period, was associated with significant renal dysfunction. However, routine monitoring of serum indices (i.e. sodium, urea, creatinine and albumin) failed to detect such renal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosaminidase↗
PubMed1994

Acute and chronic nephrotoxicity associated with immunosuppressive drugs.

Although the main immunosuppressive drugs used commonly after transplantation and in the treatment of autoimmune disease are cyclosporine and FK506, both have similar nephrotoxic properties that may limit their clinical use. The complexity of both the functional and structural characteristics of cyclosporine and FK506 nephrotoxicity strongly suggests a multifactorial process involving complex physiologic and intracellular signaling processes that have obvious implications for the design and development of new immunosuppressive drugs. This review summarizes recent concepts regarding the mechanisms responsible for the renal dysfunction related to these drugs and outlines methods of possible therapeutic intervention.

Acute Disease↗
PubMed1994

The relationship between total kidney cyclosporin A concentrations, trough drug levels and renal function in the rat following withdrawal of treatment.

Groups of 6 male rats received cyclosporin A (CsA: 20 mg kg-1 day-1) by gavage for either 4, 7, 10 or 14 days and were sacrificed 24 hours later. CsA nephrotoxicity was characterised functionally by decreased creatinine clearance rates and increased enzymuria. A significant correlation (r2 = 0.980; P < 0.01) was observed between the CsA concentration in renal tissue (4.88 +/- 2.16, 13.54 +/- 3.68, 25.71 +/- 6.59 and 36.64 +/- 6.797 micrograms g-1 kidney wet weight, [mean +/- SD] on days 4, 7, 10 and 14 respectively) and trough whole blood (TWB) CsA concentrations (0.86 +/- 0.18, 1.82 +/- 0.59, 3.35 +/- 0.52 and 3.70 +/- 1.12 micrograms ml-1, respectively) was observed. Furthermore, an apparent relationship between both renal tissue and TWB CsA concentration, the degree of renal microcalcification (MC) at the cortico-medullary junction and magnitude of the renal dysfunction was observed. In a second experiment, treatment was withdrawn after 14 days at 20 mg kg-1 day-1. Following withdrawal of treatment for 1, 4, 7, 10 or 14 days, renal tissue and whole blood CsA concentrations fell progressively from 32.23 +/- 11.23 and 3.01 +/- 0.96 (micrograms g-1 wet weight and micrograms ml-1, respectively) to 25.66 +/- 9.77 and 2.12 +/- 0.66, 10.42 +/- 0.65 and 0.78 +/- 0.23, 4.35 +/- 1.2 and 0.51 +/- 0.16, 3.98 +/- 3.76 and 0.27 +/- 0.03, and 2.58 +/- 1.56 and not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Alleviation of experimental cyclosporin A nephrotoxicity by low dose aspirin in the rat.

Groups of male Sprague-Dawley rats received either cyclosporin A (CsA; 25 mg/kg by gavage), low dose aspirin (ASP; 20 mg/kg by gavage), a combination of both, or the appropriate drug vehicles daily for 14 days. Renal structure and function were assessed on day 0 (pretreatment) and on days 7 and 14. Compared to pretreatment results, CsA nephrotoxicity was characterized by increased plasma urea and creatinine concentrations and by moderate to severe microcalcification (MC) at the corticomedullary junction by day 14. The development of nephrotoxicity was also associated with a 5-fold increase in urine thromboxane B2 (TxB2) excretion by day 10, while that of 6-ketoprostaglandin F1 alpha remained relatively constant. Although both ASP and saline (ASP vehicle) -cotreated animals demonstrated significantly lower plasma urea and creatinine concentrations compared to treatment with CsA alone, the severity of MC observed on day 14, was reduced only in the ASP cotreatment group. Though whole blood CsA concentrations were similar at around 2400 ng/mL in all experimental groups. In addition, although a 2-fold increase in urine TxB2 excretion was observed on days 7 and 10 following treatment with CsA/ASP, levels were significantly reduced compared to treatment with either CsA alone or CsA/saline (both P < 0.05).

6-Ketoprostaglandin F1 alpha↗
PubMed1993

The reversal of experimental cyclosporin A nephrotoxicity by thromboxane synthetase inhibition.

The ability of thromboxane synthetase inhibition to reverse acute cyclosporin A (CsA)-induced nephrotoxicity in the rat was investigated. CsA administration (50 mg/kg/day p.o. for 14 days) to male Sprague-Dawley rats caused a significant 50% decline in creatinine clearance rates, an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage by day 14. These changes were associated with a 5-6-fold increase in urinary thromboxane B2 excretion (from pretreatment values of 28.1 +/- 7.9 to 122.6 +/- 38.9 and 165.8 +/- 39.0 eta g/24 hr body weight on days 7 and 14, respectively). Excretion rates of 6-keto-prostaglandin F1 alpha and prostaglandin E2 were, however, unaffected by CsA administration. Co-treatment with a thromboxane synthetase inhibitor (CGS 12970; 8-[3-methyl-2-(3-pyridyl)-1-indolyl]-octanoic acid) from day 7 (10 mg/kg/day) normalized thromboxane B2 excretion, resulted in creatine clearance rates which were similar to pretreatment values on days 10 and 14, reduced NAG enzymuria on day 10 and prevented acute proximal tubular vacuolation. However, the severity of chronic CsA nephrotoxicity, namely chronic tubular damage and microcalcification at the corticomedullary junction, was not diminished by the thromboxane synthetase inhibition. These results demonstrate that (i) elevated thromboxane synthesis plays an important role in the development of acute CsA nephrotoxicity and (ii) that different and/or additional mechanisms are involved in the pathogenesis of chronic nephrotoxicity.

Animals↗
PubMed1993

Physiological variations in the urinary excretion of pyridinium crosslinks of collagen.

To further validate measurements of the pyridinium crosslinks of collagen as indices primarily of bone resorption in arthritis and other diseases, the effects of day-to-day and nyctohemeral parallel variations, and of renal impairment have been studied. Day-to-day variations measured over 3 weeks were between 16 and 24% for a group of post-menopausal women. Nyctohemeral variations in crosslink excretion of 10-15% were recorded. Although crosslink excretion relative to creatinine was generally higher in the morning than in the evening, no consistent pattern was observed between healthy male and female volunteers and a group of patients with OA or RA. For patients with impaired renal function, with or without arthritis, there was no correlation between crosslink excretion and either creatinine clearance rates or urinary N-acetyl glucosaminidase activity. These results suggested that there was no direct relationship between renal function, at the glomerular or tubular level, and crosslink excretion.

Adult↗
PubMed1993

The effects of retinoids and terbinafine on the human hepatic microsomal metabolism of cyclosporin.

Following the observation of increased trough whole blood cyclosporin A (CyA) concentrations and reduced renal function in a patient with recalcitrant generalized pustular psoriasis treated with a combination of CyA and etretinate, the effect of vitamin A analogues on human microsomal cytochrome P450-dependent CyA metabolism was investigated in vitro. In addition, the effect of terbinafine, a new allylamine antifungal agent, was also tested. Etretinate, its major metabolite acitretin, and isotretinoin, each at a single concentration of 100 microM, inhibited total hepatic microsomal CyA metabolism to a similar extent (33-45%, compared with control values). The generation of total primary and total secondary CyA metabolites was also inhibited to a similar extent by each of the retinoids. Conversely, terbinafine was without significant effect on CyA metabolism in vitro. The results, which suggest that inhibition of hepatic CyA metabolism by retinoids may contribute to increased circulating CyA concentrations, are discussed in relation to other potential drug interactions, and to the use of etretinate in reducing the CyA administered dose.

Acitretin↗
PubMed1993

Lithium clearance measurements during recombinant interleukin 2 treatment: tubular dysfunction in man.

Renal tubular function was evaluated in nine patients undergoing recombinant interleukin 2 (rIL2) treatment for metastatic colorectal carcinoma. A lithium clearance technique was used and the activities of the lysosomal enzyme N N-acetyl-beta-D-glucosaminidase were also measured in the patients' urine, before treatment, during treatment, and then 2 days and 23 days after rIL2 therapy had finished. Significant reductions in clearances of creatinine, sodium, and lithium were observed. The fractional excretions of sodium and lithium were also reduced. Twenty-three days following cessation of rIL2 treatment, there was still a significant reduction in creatinine clearance compared with pretreatment values (p < .01). The clearances of sodium and lithium were also reduced compared with pretreatment values although this did not achieve significance. The fractional reabsorption of sodium and water by the proximal nephron increased during rIL2 treatment, from 0.707 +/- 0.030 (pretreatment) to 0.793 +/- 0.043. This increased reabsorption of sodium and water persisted, rising to 0.849 +/- 0.029, 2 days following cessation of treatment (p < .001, means +/- SEM). Twenty-three days later this had returned toward the pretreatment value, being 0.781 +/- 0.036. The fractional reabsorption of sodium by the distal nephron was also significantly elevated, both during and 2 days after completing rIL2 treatment. Twenty-three days after cessation of rIL2, this value had returned to the pretreatment value. However, in contrast, the fractional reabsorption of water by the distal nephron demonstrated no change during rIL2 treatment, but 2 days posttreatment was significantly reduced and remained low for a further 3 weeks.

Acetylglucosaminidase↗
PubMed1993

Comparative effects of rapamycin, FK 506 and cyclosporine on antibody production, lymphocyte populations and immunoglobulin isotype switching in the rat.

The immunosuppressive activity and comparative efficacy of rapamycin (RAPA), FK 506 and cyclosporine A (CsA) were investigated in rats following immunization with either xenogeneic sheep red blood cells (SRBC) or allogeneic blood transfusion. RAPA formulated in a polyethylene glycol vehicle, and at a dose of 1.5 mg.kg-1 i.p., was relatively ineffective when compared with FK 506 (1 mg.kg-1) or CsA (15 mg.kg-1) in suppressing antibody production to SRBC. Like FK 506 and CsA however, RAPA proved highly effective in suppressing both the B lymphocytosis and the increase in circulating major histocompatibility complex class II+ cells observed following immunization. All three immunosuppressants caused thymic medullary atrophy, with evidence of epithelial cell damage and increased macrophage phagocytic activity. Administered i.m. (3 mg.kg-1 in olive oil), RAPA was also highly effective in suppressing 1 degree alloantibody responses to MHC class I antigens following blood transfusion. Unlike FK 506 and CsA however, a short (14-day) course of RAPA following 1 degree immunization (transfusion) did no suppress 2 degree alloantibody responses elicited 6 weeks later. Moreover, RAPA did not prevent immunoglobulin isotype switching as observed with FK 506 and CsA. This may reflect the distinct mechanisms of action of RAPA and the latter two agents on T-cell activation/proliferation. Further comparative and combination studies of RAPA with in particular, CsA, are required to further explore to potential of RAPA as an immunotherapeutic agent.

Animals↗
PubMed1993

Chronic cyclosporin A (CsA) nephrotoxicity in the rat: the effect of calcium blockade with verapamil.

Renal structure and function were assessed in groups of male Sprague-Dawley rats, either surgically intact (SI) or nephrectomized (N), treated with either CsA alone (20 mg/kg, p.o.) or in combination with verapamil (VER; 10 mg/kg/day, i.p.) daily for up to 28 days. Compared to vehicle treated controls, reduced creatinine clearance rates (CCR, mean +/- s.e.m.) were noted following CsA treatment in Sl animals on days 21 and 28 (279 +/- 4 vs 196 +/- 20 and 296 +/- 13 vs 122 +/- 13 ml/h/kg, respectively, both P < 0.05). However, CCR was around 60% of pretreatment values in all N animals from day 7 onwards. A two to three-fold elevation in urinary N-acetyl-beta-D-glucosaminidase activity was noted from day 7 to 28 in all CsA treated animals. In addition, a similar severity of both renal tubular basophilia and corticomedullary microcalcification (but not proximal tubular vacuolation), was noted at all time points in animals receiving CsA alone. Co-treatment with VER reduced the severity of microcalcification in CsA groups, particularly N animals, increased CCR on day 14 in the Sl (196 +/- 23 vs 391 +/- 64) and days 21 and 28 in N (141 +/- 14 vs 357 +/- 32 and 152 +/- 28 vs 261 +/- 20) groups, respectively but had no effect on the magnitude of enzymuria, despite significantly increased trough whole blood CsA levels (20-30%) in both Sl and N groups. These results indicate that calcium blockade reduces both structural and functional features of chronic CsA nephrotoxicity.

Animals↗
PubMed1992

Interleukin 2 therapy in cancer: identification of responders.

C-reactive protein (CRP) levels in serum were measured in fifteen patients with metastatic colorectal carcinoma, prior to and during treatment with a continuous intravenous infusion of rIL.2. Patients were subsequently classified as responders or non-responders to this therapy. Baseline serum CRP levels, prior to treatment, were significantly lower in the responders (range < 2-8 mg l-1) when compared with the non-responders (range 7.5-116 mg l-1), P = 0.004. Furthermore, the responding patients demonstrated significantly and grossly elevated CRP stimulation indices (SI) compared with non-responders at different time intervals during the rIL2 infusion. At the cessation of rIL2 therapy, the CRP stimulation index was 31.3 +/- 9.3 in the responders, and only 1.6 +/- 0.3 in the non-responders (means +/- s.e.m, P = 0.014). These findings suggest that it is possible to predict those cancer patients who are most likely to respond to and benefit from rIL2 therapy, either prior to the commencement of or during the first course of rIL2.

Adult↗
PubMed1992

Glomerulotubular function in patients undergoing moderate surgical stress.

Glomerular function and renal tubular function assessed by measurements of creatinine clearance rates (CCR), lithium clearance rates (CLi, and N-acetyl-beta-D-glucosaminidase (NAG) enzymuria were measured immediately prior to and within 24 h of operation (average operative time 150 min) in 16 patients undergoing a moderate surgical stress. Although serum creatinine concentrations and CCR were similar pre- and postsurgery at 105 +/- 21 and 108 +/- 21 mumol/L and 108 +/- 67 and 110 +/- 59 mL/min/100 kg body weight (mean +/- SD), respectively, both CLi and NAG were significantly increased following the surgical insult. CLi was increased from 19.7 +/- 6.1 to 31.7 +/- 16.7 mL/min/100 kg (p less than 0.01) and NAG from 71 +/- 58 to 164 +/- 10 U/mmol urinary creatinine (p less than 0.001). In addition, the absolute distal tubular reabsorption of sodium and water increased from 18.3 +/- 5.9 and 15.8 +/- 9.7 to 30.6 +/- 16.4 and 27.6 +/- 12.2 mL/min/100 kg body weight (both p less than 0.05), respectively. These results indicate early postoperative renal tubular dysfunction following a moderate surgical stress, undetected by conventional screening.

Aged↗