Conflict of interest: will it ever end?

Despite the inclusion of investigator-industry pecuniary and non-pecuniary associations in published clinical trials, the benefit of such disclosures may be limited. Two recent pivotal phase III drug studies that raised conflict of interest issues are discussed. It is recommended that in the future, a firewall should be erected between industry and investigators.

Basic concepts in meta-analysis: A primer for clinicians.

With the expanding volume of medical literature, meta-analysis, a form of systematic review, has become indispensable for clinicians for evidence-based decision making. While the number of meta-analyses has substantially increased during recent years, there are still controversial issues regarding their methodology, interpretation and clinical application. In this review, the basic concepts of meta-analysis have been discussed from a clinician's perspective in order to facilitate its understanding, appraising and applicability in clinical practice. Although randomised controlled trials are the usual source for meta-analysis, observational studies are also being increasingly considered for meta-analysis. Like every other research design, meta-analysis starts with formulating a question, followed by searching for related data, based on predefined criteria and strategies. Inclusion of studies must be carried out with careful consideration of their quality and assessment of homogeneity using graphical means as well as statistical tools such as Q statistics, I(2) statistics and meta-regression. The pooled effect size is commonly calculated using either a 'fixed effect model' or 'random effect model'. Publication bias and other source of bias should be investigated and the impact of potential confounders should be eliminated as required. Given the above-mentioned considerations, meta-analysis can provide a more precise estimate of an effect size to be used in clinical decision making.

Medication accuracy and general practitioner referral letters.

Prescriber medication communication is a Quality Use of Medicines barrier. Medication information in General Practice (GP) referral letters to a physician was evaluated. Accuracy of medications taken and drug dose was respectively 63% and 84%, an overall accuracy rate of 58%. Complementary/over-the-counter medication documentation occurred in 26% of the letters. To avoid medical mismanagement, physicians must validate all GP medication lists regardless of their apparent comprehensiveness.

Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially depending on length of fluoxetine administration, which could contribute in explaining the slow onset of antidepressant activity observed with selective serotonin reuptake inhibitors.

In vitro activity of LY393558, an inhibitor of the 5-hydroxytryptamine transporter with 5-HT(1B/1D/2) receptor antagonist properties.

1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulphonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558) is a potent inhibitor of [3H]5-hydroxytryptamine ([3H]5-HT) uptake into rat cortical synaptosomes (pIC(50)=8.48+/-0.12). It produces a dextral shift of the 5-HT dose-response curves for the binding of GTPgamma[35S] to human 5-HT(1B) (pK(b)=9.05+/-0.14) and 5-HT(1D) (pK(b)=8.98+/-0.07) receptors and inhibits the contractile response of the rabbit saphenous vein to the 5-HT(1B/D) receptor agonist, sumatriptan (pK(b)=8.4+/-0.2). In addition, it is an antagonist at the 5-HT(2A) (pK(i)=7.29+/-0.19) and 5-HT(2B) (pK(i)=7.35+/-0.11) receptors. Presynaptic autoreceptor antagonist activity was demonstrated by its ability to potentiate the K(+)-induced outflow of [3H]5-HT from guinea pig cortical slices (pEC(50)=7.74+/-0.05 nM) in which the 5-HT transporter had been inhibited by a maximally effective concentration of paroxetine. It is concluded that LY393558 should be an effective antidepressant with the potential to produce an earlier onset of efficacy than selective serotonin uptake inhibitors.

Pharmaceutical industry-sponsored meetings: good value or just a free meal?

Although the role of the pharmaceutical industry in continuing medical education (CME) has been debated for many years, industry CME funding continues to increase. Because of concern about the educational quality of industry CME, the Hunter Postgraduate Medical Institute (HPMI), an independent Newcastle and Hunter Valley CME provider, evaluated the use and quality of industry CME as reported by rural and urban general practitioners, physicians and psychiatrists. Furthermore, clinicians were asked if they supported increased industry-funded independent CME. Sixty-two per cent of general practitioners and 71% of psychiatrists attended at least three industry-organized meetings each year, compared with 24% of physicians. Twenty-five per cent of general practitioners attended five or more such meetings. Industry meetings were judged to be of good to excellent quality by 81% of generalists, 79% of physicians and 87% of psychiatrists. All clinical groups ranked the topic and then speaker as the most important reason for attending, with CME points, venue and the sponsor ranked lowest. Eighty to 90% of doctors supported a greater role of industry-funded independent CME. Despite the absence of current data on the use and perceived benefits of industry CME, these preliminary results suggest that industry CME is playing an increasingly important role in clinician education. However, many clinicians and industry representatives support a greater role by independent postgraduate organizations in industry-sponsored CME.

LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone.

The potential antidepressant, LY367265 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3, 6-dihydro-1(2H)-pyridinyl]ethyl]-5,6-dihydro-1H,4H-[1,2, 5]thiadiazolo[4.3.2-ij]quinoline-2,2,-dioxide) has been shown to have a higher affinity for the 5-hydroxytryptamine (5-HT) transporter (K(i)=2.3 nM) and 5-HT(2A) (K(i)=0.81 nM) receptor than the clinically effective antidepressant, nefazodone. It is a potent inhibitor of [3H]5-HT uptake into rat cortical synaptosomes (IC(50)=3.1 nM) and shows selectivity over that for [3H]noradrenaline (IC(50)>1000 nM). It potentiates potassium-induced [3H]5-HT outflow from prelabelled guinea pig cortical slices both in the presence (EC(50)=950 nM) and absence (EC(50)=250 nM) of a saturating concentration of the 5-HT transport inhibitor, paroxetine, indicating a low level of activity at the 5-HT(1B/1D) autoreceptor. These studies indicate that LY367265 is a putative antidepressant which, because of its 5-HT(2A) receptor antagonist activity, has the potential to produce less sleep disturbance and sexual dysfunction than selective serotonin uptake inhibitors.

Distribution of the voltage-dependent calcium channel alpha1G subunit mRNA and protein throughout the mature rat brain.

The molecular identity of a gene which encodes the pore-forming subunit (alpha1G) of a member of the family of low-voltage-activated, T-type, voltage-dependent calcium channels has been described recently. Although northern mRNA analyses have shown alpha1G to be expressed predominantly in the brain, the detailed cellular distribution of this protein in the central nervous system (CNS) has not yet been reported. The current study describes the preparation of a subunit specific alpha1G riboprobe and antiserum which have been used in parallel in situ mRNA hybridization and immunohistochemical studies to localize alpha1G in the mature rat brain. Both alpha1G mRNA and protein were widely distributed throughout the brain, but variations were observed in the relative level of expression in discrete nuclei. Immunoreactivity for alpha1G was typically localized in both the soma and dendrites of many neurons. Whilst alpha1G protein and mRNA expression were often observed in cells known to exhibit T-type current activity, some was also noted in regions, e.g. cerebellar granule cells, in which T-type activity has not been described. These observations may reflect differences between the subcellular distribution of channels that can be identified by immunohistochemical methods compared with electrophysiological techniques.

Hospital blood pressure measurement: staff and device assessment.

Evaluation of the ability of clinical staff to measure blood pressure as well as the functional state of hospital sphygmomanometers has consistently demonstrated marked deficiencies. In this study, the working order of all sphygmomanometers (manual and automated) in a teaching hospital was evaluated. Nursing staff were tested on their knowledge and use of such devices and were also asked to estimate the blood pressure from videotape. The accuracy of a commonly used automated device, Dinamap 8100, was also measured. Of 543 manual sphygmomanometers, 14% were in perfect working order although portable devices were more likely to be functional (47% of 36 units). In contrast, all 135 automated portable devices were in perfect working order although service requirements were seldom met. The mean time since last service was 18 months. There appeared to be an inverse correlation between the availability of automated and manual devices and the maintenance of wall-mounted bedside sphygmomanometers. Staff knowledge about manual devices was adequate as was their ability to accurately measure blood pressure using standardised videotape. Forty-two per cent of 31 nurses who completed the test were correct in 9 of 12 blood pressures. A comparison of this result with a comparable group of nurses tested in 1990 did not detect a significant change in competence. Direct evaluation of the commonly used Dinamap 8100 in 47 hospital patients demonstrated a poor correlation with a mercury sphygmomanometer with a D grade (fail) for systolic and a C grade for diastolic pressure. In summary, maintenance of manual sphygmomanometers was very poor, probably due to their lack of use by clinical staff. This was particularly true for units attached to bedside walls. Nursing staff demonstrated significant deficiencies in manual sphygmomanometer use although their skills were similar to those measured several years earlier. Because of the demonstrated inaccuracy of the Dinamap 8100 automated device, the strong trend towards the use of automated devices instead of manual sphygmomanometers within hospitals cannot be supported.

Antihypertensive drug treatment: a comparison of usual care with self blood pressure measurement.

Blood pressure self-measurement is increasing in most communities and yet its role in the management of hypertension is poorly understood. This study was devised to evaluate the behaviour of doctors in general practice when treating patients with poorly controlled essential hypertension who use self-measurement. Patients, most of whom were already taking antihypertensive medications were commenced on perindopril or indapamide at their doctor's discretion and were randomly allocated to self-measurement (SM) using an OMRON HEM706 oscillometric device or a continuation of their usual care (UC) over an 8-week period. This was an observational study without any specific or set treatment goals for the doctor to follow. Sixty of 62 subjects completed the study and the two groups were equally matched for age, body mass index, gender, and blood pressure (BP). While additional perindopril or indapamide produced a significant fall in BP in both groups over the study period, the systolic pressure remained significantly higher in the SM group (sitting 148 +/- 3 compared with 142 +/- 3; 145 +/- 3 compared with 138 +/- 3 mm Hg respectively; P < 0.05). Twenty-four hour and daytime ambulatory monitor systolic pressures were also significantly higher in the SM group. Differences in diastolic BP were not statistically significant. Furthermore, SM patients were less likely to have their medications increased and more likely to have them reduced or ceased. Doctors and patients found self-measurement convenient and useful. This study suggests that doctors prescribing decisions are influenced by evidence from self-measurement of BP with consequential increases in office BP related to reduced drug use. While self-BP measurement can offer reassurance about adequacy of control when away from a physicians office, our best evidence of understanding target blood pressures comes from large randomised studies using office blood pressures as an end-point. There is an urgent need for further study to provide arbitration between self-measurement and office blood pressures although each measurement must contribute to the management of hypertension.

Chronic calcitonin administration and renal calcium transport in the rat.

1. While calcitonin (CT) has now been clearly demonstrated to be a renal Ca2+-conserving hormone and may share similar transport mechanisms with parathyroid hormone (PTH), the effect of prolonged CT exposure on renal Ca2+ transport has not been evaluated. 2. Consequently, a submaximal and maximal Ca2+-conserving concentration of human CT was infused into groups of anaesthetized acutely thyroparathyroidectomized rats that had been treated with twice daily subcutaneous human (h) CT at a low or high dose or vehicle for 12 days. 3. The maximal hCT infusion (10 microg bolus and per hour) produced a marked inhibitory effect on renal Ca2+ excretion in vehicle-treated rats, with the fractional excretion rate of Ca2+ being reduced from 4.49+/-0.31 to 139+/-0.23% (P<0.001). However, in rats pretreated with high concentrations of hormone (0.25 microg hCT) twice daily for 12 days, marked Ca2+ conservation was measured (fractional excretion 1.09+/-0.18%), which was not altered by the additional intravenous administration of maximal hCT. 4. Renal Mg2+ transport was similarly altered by hCT administration, without any evidence that prolonged CT inhibited renal Mg2+ transport. The increase in glomerular filtration rate caused by hCT also appeared to persist with repeated hormone administration. The fractional excretion of Na+ and PO4 was significantly increased by high- but not low-dose hCT treatment and was not altered by the addition of a maximal hormone dose at day 12. 5. The present study failed to demonstrate any down-regulation of the response to prolonged hCT administration when renal Ca2+ and Mg2+ transport was measured. If renal escape does occur with CT, as has been suggested but not proven with PTH, other mechanisms, such as hormone production or release, may be responsible.

Calcitonin and human renal calcium and electrolyte transport.

While original studies in man and animals suggested that calcitonin increases renal Ca excretion, subsequent studies in the rat have confirmed calcitonin as a renal Ca-conserving hormone. In this study three concentrations of calcitonin (0.01, 0.1 and 1.0 mg prime and per hour) were infused into humans made acutely hypercalcemic to inhibit endogenous PTH secretion. Calcitonin promptly inhibited the hypercalcemia in a dose-dependent way and also reduced fractional Ca excretion. In addition calcitonin, particularly at 0.1 and 1.0 mg concentrations, increased absolute Ca and Mg reabsorption. No significant effects of calcitonin on Na and K transport were noted with these concentrations; however, the highest calcitonin concentration produced a small but significant increase in fractional phosphate excretion (0.6 +/- 0.2 to 1.0 +/- 0.3%; p < 0.05). Creatinine clearance was also increased with the highest calcitonin concentrations. It is concluded that in man calcitonin like PTH is a renal Ca- and Mg-conserving hormone.

The contributions of glycosaminoglycans, collagen and other interstitial components to the hydraulic resistivity of porcine aortic wall.

A pressure-driven flux of water occurs across the arterial wall in vivo. We have investigated the role of several interstitial components in determining the resistance of the wall to this flow. Pieces of porcine thoracic aorta were modified by thermal denaturation, enzymatic digestion or disruptive chemical treatments. The effect of these procedures on the wall content of glycosaminoglycans, collagen and elastin was determined by biochemical assay of uronic acid and hydroxyproline. Effects on hydraulic conductivity were measured by using a flow cell in which tissue was free to deform under applied pressure. Untreated tissue showed considerable variation in uronic acid content but conductivities were substantially less variable and averaged 0.75 x 10(-12) cm4/dyne.s. In tissue autoclaved for < 1 h, resistivity increased, possibly because interstitial components had been denatured but not removed from the wall. After longer periods, resistivity decreased by a factor of one hundred. More specific treatments showed that resistivity decreased by up to a factor of ten when glycosaminoglycans were removed and by a similar factor when collagen was removed. Tissue in which both were removed showed a hundred-fold decrease in resistivity. As with tissue subjected to prolonged autoclaving, the resistivity was still an order of magnitude higher than that of alkali- or acid-extracted elastin despite an apparently similar composition, suggesting the existence of a non-assayed component with important properties. The resistivity of the samples was decreased further by treatment with chymotrypsin, consistent with this component being microfibrillar protein.

Hypertension treatment compliance: what do patients want to know about their medications?

While poor drug compliance is a significant impediment to the effective treatment of hypertension, knowledge of what patients wish to know about their medications in order to improve compliance is very limited. To develop a preliminary understanding of patients' medication requirements and expectations, a simple 30-item questionnaire was developed and administered to 66 patients who were either taking antihypertensive drugs, or about to commence antihypertensive drug treatment. Ninety percent of patients wanted to know about all possible side effects of medications as well as the most likely side effects. Ninety-six percent wanted to know if their drug treatment would keep them well. In addition, most patients wanted to avoid multiple medications, were concerned about the prospect of life-long treatment, and were worried about potential drug interactions. Effects of the drugs on their lifestyles as well as any lifestyle changes required to augment drug therapy were other issues of concern. The elderly were less interested in many of these issues. A strong desire for further knowledge about their disease was noted in most subjects (82%). If compliance with medication therapy is to be improved, a better understanding of patients' concerns and fears about medications is required, particularly in a relatively asymptomatic disease like hypertension.

Effect of diacetyl rhein on the development of experimental osteoarthritis. A biochemical investigation.

OBJECTIVE: To investigate the effect of diacetyl rhein (DAR) on the synthesis, turnover and composition of cartilage in an experimental model of osteoarthritis in beagle bitches. DESIGN: Osteoarthritis was induced in mature beagle bitches by the transection of the cranial cruciate ligament. Six animals received DAR 20 mg/kg daily for 11 weeks. A matched group received empty capsules daily for the same period. At 11 weeks, articular cartilage was examined for the ratio of the 6:4-sulfated disaccharides of chondroitin and the tissue concentration of hydroxyproline and glycosaminoglycan. In addition, labeling studies were performed to estimate the effect of DAR on proteoglycan synthesis and turnover. RESULTS: DAR had no effect on body weight or food consumption but induced a mild diarrhea and slightly increased the incidence of vomiting. DAR tended to reduce proteoglycan synthesis, however, DAR did reduce proteoglycan turnover in the femoral cartilage. DAR produced changes in the composition of the osteoarthritic cartilage that could only partly be accounted for by changes in hydration and/or swelling. In addition, it was noted that induction of osteoarthritis increased the ratio of chondroitin 6-sulfated to chondroitin 4-sulfated disaccharides; DAR reduced the ratio in tibial plateau cartilage from osteoarthritic joints compared with untreated tissue from osteoarthritic joints. DAR showed moderate reduction on the biosynthesis of proteoglycans. DAR also produced a reduction in proteoglycan turnover from all anatomical areas compared with non-treated controls in both the lateral and medial femoral condyles. CONCLUSIONS: DAR was well tolerated by the experimental animals, but did not produce significant changes in the synthesis or turnover of proteoglycans. The slight reduction in proteoglycan synthesis may prove to be biologically significant after chronic dosing. DAR's effects on the hydroxyproline and glycosaminoglycan content suggest, however, that it must influence the swelling of cartilage and loss of glycosaminoglycan. This indicates that small changes can translate, to significant differences in cartilage composition over an 11-week time period.

Mechanism of lithium-induced polyuria in the rat.

While many studies have demonstrated a nephrogenic diabetes insipidus syndrome (NDI) with prolonged lithium (Li) treatment, experiments in the isolated rat papillary collecting duct have suggested that the defect may be due to a circulating factor that inhibits the action of arginine vasopressin (AVP). Since Li-treatment can produce a form of hyperparathyroidism and parathyroid hormone (PTH) can act as a partial agonist to AVP, in vivo and in vitro studies were performed on rats made polyuric by daily intraperitoneal (i.p.) Li (4 mmol/kg) treatment. Li-treatment for three weeks produced an increase in PTH (194 +/- 20 compared with 118 +/- 18 pg/ml in control rats; P < 0.01) as well as an increase in the plasma calcium concentration (2.38 +/- 0.05 compared with 2.25 +/- 0.04 mmol/liter; P < 0.05). Clearance studies were performed on water loaded Li-treated and control rats, and the defect in urine concentration was only observed with a low physiological concentration of AVP (10 mU/kg body wt over 5 min). Maximal urine osmolality was 328 +/- 31 compared with 613 +/- 81 mOsm/kg (P < 0.05) in controls. There was no detectable difference with a prolonged maximal physiological AVP concentration (10 mU bolus and 50 mU/kg body wt per hr) and papillary solute concentrations were unchanged. When Li-treated rats had been parathyroidectomized (PTX), a significant difference in urine concentration with the low AVP concentration could not be demonstrated when compared to non-PTX control rats. In the isolated papillary collecting duct preparation a medium was used that contained fresh plasma from Li-treated or control rats, both intact and PTX. Experiments using plasma from Li-treated intact rats produced only a 25.4 +/- 5.1% increase in diffusional water permeability with the addition of AVP (200 microU/ml) compared to 52.6 +/- 9.0% in control rats (P < 0.01). However, when plasma from Li-treated PTX rats was used, the AVP induced increase in water permeability (54.7 +/- 11.2%) was not significantly different from that observed in PTX control rats. These studies show that the NDI-like defect in Li-treatment is small and easily overcome by higher concentrations of AVP and suggests that the concentration defect is at least in part due to increased circulating levels of PTH acting as a partial agonist to AVP and thereby inhibiting its hydroosmotic action.

The investigation of glycosaminoglycan mimotope structure using capillary electrophoresis and other complementary electrophoretic techniques.

We have used various electrophoretic techniques to analyse glycosaminoglycan structure. Capillary electrophoresis has been particularly useful in the determination of the sulphation of glycosaminoglycans (GAG) and the sulphation of partly desulphated glycosaminoglycans produced by methanolysis. This, in conjunction with preparative electrophoresis and enzyme linked immunosorbent assay (ELISA) has permitted us to ascertain the length of the oligosaccharide required for binding and sulphate ester groups required for optimal binding and those essential for antibody binding. From these preliminary studies, we have demonstrated that the minimum length of oligosaccharide required for binding was about 12-14 monosaccharides in length. It appears likely that 6 sulphation is required for strong binding but 4 sulphation is not involved in mimotope binding. We propose on the basis of this evidence that the mimotope does not contain 4-sulphate residues but 3-4 6-sulphate ester groups are essential for binding.

Acute effect of ethanol on renal electrolyte transport in the rat.

1. Despite human and animal studies, the direct effect of ethanol on renal water and electrolyte transport is poorly understood. The acute effect of increasing plasma concentrations of ethanol was evaluated in a water diuretic anaesthetized rat model which inhibits endogenous arginine vasopressin (AVP) release. 2. Ethanol at a plasma concentration of 1.69 +/- 0.28 mmol/L produced an immediate increase in urine flow (174 +/- 11 microL/min pre-ethanol and 189 +/- 13 and then 206 +/- 12 microL/min during the ethanol infusion; P < 0.01) as well as an increase in fractional sodium excretion (0.17 +/- 0.04 to 0.28 +/- 0.05 and 0.27 +/- 0.05%; P < 0.01). There was also a brief phosphaturia. These increases in electrolyte excretion had returned to control values by 20 min despite a further increase in the plasma ethanol concentration. 3. The urinary excretion of potassium, calcium and magnesium was not altered nor was glomerular filtration rate or renal plasma flow. 4. Ethanol at a mean concentration of 1.60 mmol/L did not alter the action of a maximal concentration of AVP (75 ng/kg) on water or electrolyte transport. However, the antidiuretic effect of a submaximal concentration of AVP (7.5 ng/kg) was augmented by ethanol at concentrations of 1.63 and 0.98 mmol/L. 5. These studies suggest that the ethanol induced diuresis commonly ascribed to inhibition of AVP secretion may also be due to other intrarenal effects of ethanol, possibly acting within the proximal tubule. These results also confirm recent in vitro findings that while ethanol does not inhibit the action of a maximal concentration of AVP, it does modulate the effects of lower AVP concentrations.

An in vivo investigation of the effect of anthraquinones on the turnover of aggrecans in spontaneous osteoarthritis in the guinea pig.

We present details of a method which allows for the determination of chondroitin sulphate turnover in vivo using the guinea pig. Such methods have been utilised to examine the effects of diacetyl rhein, a compound with purported anti-osteoarthritic activity, and several related anthraquinone analogues on the turnover of chondroitin. Since the guinea pig develops spontaneous osteoarthritis, this may give useful information on the potential for such compounds to inhibit the progression of osteoarthritis. The results show that several of the anthraquinones are capable of reducing the turnover of chondroitin 4- but not 6-sulphate. This may indicate potential mechanisms for the breakdown of guinea pig cartilage aggrecans. We propose that these techniques could be useful for the screening of chemical agents with useful activity against osteoarthritis.