Regulatory aspects of new medicines targeted at treatment of autoimmune diseases.

Autoimmune diseases comprise a diverse group of clinical dis orders that result from the body's adaptive immune system reacting against its own tissues.(1) Conversely, autoinflammatory disorders encompass a more limited group of diseases distinguished by recurrent episodes of inflammation but in the absence of high-titer autoantibodies and antigen-specific T cells.(2) The past 15 years have seen a tremendous growth in the development of highly effective treatments for these diseases.

Long-term oral complications of allogeneic haematopoietic SCT.

This study assessed the incidence of long-term oral complications in 88 survivors of allogeneic haematopoietic cell transplantation (HCT). Patients examined were between 6 months and 6 years post-HCT and aged from 19 to 65 years. Subjects were investigated for both the subjective and objective features of long-term adverse oral effects of HCT. The most common oral symptoms reported were xerostomia (44%, n=39) and reduction in taste (20%, n=18). Only a minority of patients (15%) reported that oral disease had a significant adverse impact upon their quality of life. The majority of patients (53%) had clinical markers of oral chronic GVHD (cGVHD). The most frequently identified feature was salivary hypofunction, with 34% of subjects demonstrating a reduction in stimulated saliva. Oral mucosal changes consistent with cGVHD affected 21% of subjects. Oral cGVHD commonly occurs after allogeneic HCT, often coexists with cutaneous, hepatic or ocular cGVHD and may lead to debilitating symptoms. Transplant type and pre-existing acute GVHD are the major risk factors for oral cGVHD. The identification of risk factors specific for oral cGVHD may allow clinicians some foresight into identifying patients at high risk of developing oral cGVHD and encourage attention to education, regular oral surveillance and rigorous preventative oral health strategies both pre- and post-transplant.

A deceptive case of amyloid myopathy: clinical and magnetic resonance imaging features.

Amyloid myopathy is a well-described, increasingly recognized clinical entity. Similar to inflammatory myopathies, amyloid myopathy presents with proximal muscle weakness and can be associated with elevated levels of muscle enzymes. We report the case of a 58-year-old woman who, at presentation to her physician with proximal muscle weakness and congestive heart failure, was antinuclear antibody positive and had muscle biopsy findings "consistent with inflammatory myopathy." She was referred to Johns Hopkins University Medical Center with the diagnosis of polymyositis. Further investigation revealed a monoclonal gammopathy, a unique patterning of subcutaneous fat reticulation and hypodense bone marrow changes on magnetic resonance imaging (MRI), and an endocardial biopsy sample that was positive for light chain amyloid deposition. Paraffin sections of the muscle biopsy sample from the time of her original presentation were obtained, and Congo red staining showed diffuse amyloid deposition throughout the sample, but no inflammation. This case not only illustrates that proximal muscle weakness due to primary amyloid myopathy (as found in light chain amyloidosis and transthyretin amyloidosis) can mimic that of polymyositis, but also shows that unique findings on MRI can alert the clinician to the diagnosis of amyloidosis prior to muscle biopsy.

Enhancement of lithium elimination by multiple-dose sodium polystyrene sulfonate.

OBJECTIVE: To determine whether multiple doses of sodium polystyrene sulfonate (SPS) enhance the elimination of IV-administered lithium (Li). METHODS: The study was a placebo-controlled, investigator-unblinded, murine trial of multiple doses of SPS on serum Li concentrations. Seventy-five male CD-1 mice were given IV pretreatment with LiCl (125 mg/ kg) followed by gavage treatments with SPS (5 g/kg/dose) 20, 40, 90, 150, and 210 minutes after LiCl (experimental group) or deionized water at equivalent times (control group). Subgroups of each treatment group were sacrificed at 1, 2, 4, and 6 hours after LiCl administration and blood was collected for Li analysis. RESULTS: Statistical analyses indicated that the SPS group had lower serum Li concentrations overall than did the control animals. This difference was apparent at the 2-, 4-, and 6-hour time points. CONCLUSION: In this murine model, repetitive doses of orogastric SPS enhanced the elimination of parenterally administered Li.

Sodium polystyrene sulfonate treatment for lithium toxicity: effects on serum potassium concentrations.

OBJECTIVE: To examine the effects of sodium polystyrene sulfonate (SPS) on serum potassium (K) concentrations in mice pretreated with parenteral lithium (Li). METHODS: A placebo-controlled murine model trial of SPS therapy following IV Li was performed. Sixty male CD-1 mice weighing 18-22 g were administered either IV LiCl (125 mg/kg) or a control solution (normal saline). Half of the mice in each of these groups were then given orogastric water 20, 40, 90, 150, and 210 minutes after LiCl or normal saline; the other half received SPS (5 g/kg/dose) at equivalent times. Subgroups of each of these four groups were sacrificed at one, two, and six hours after pretreatment and the serum was analyzed for K concentration. Serum K concentrations for the various groups were compared with analysis of variance and Newman-Keuls tests for the comparison of multiple means. RESULTS: A statistically significant reduction of serum K concentrations occurred in the animals that received SPS treatment following either IV saline or LiCl solutions. The degree of K reduction that resulted from the combination of LiCl and SPS treatment (35% reduction at six hours, compared with the placebo-treated controls) was larger than that which resulted from either IV Li with oral water (15% reduction) or IV saline with oral SPS (20% reduction). CONCLUSIONS: These findings suggest that development of hypokalemia may represent a potential limitation in the use of SPS in the treatment for Li toxicity.

Effect of delayed treatment with sodium polystyrene sulfonate on serum lithium concentrations in mice.

OBJECTIVES: To determine the efficacy of sodium polystyrene sulfonate (SPS) in lowering serum lithium (Li) concentrations. Specifically, to determine the effects of both different doses of SPS and different times to treatment with SPS on serum Li levels. METHODS: The study was a controlled, single-dose murine trial of SPS on serum Li levels. Male CD-1 mice (n = 525) were given orogastric LiCl and then divided into three main treatment groups: group SPS received a single orogastric administration of SPS in a dose of 5 gm/kg body weight at either 0, 15, 30, 45, or 90 minutes after LiCl; group half-SPS received a single orogastric administration of SPS in a dose of 2.5 gm/kg body weight at times equivalent to those of group SPS; and the control group received orogastric deionized water in a volume equivalent to that of group SPS at 0, 15, 30, 45, or 90 minutes after LiCl. Subgroups of seven to ten mice in each of the four treatment groups were sacrificed at one, two, four, and eight hours after administration of LiCl, and their blood was analyzed for Li concentration. RESULTS: 1) Single doses of SPS significantly lowered serum Li concentrations; 2) this effect was dose-related; 3) the delays in administration of SPS used in this study did not significantly reduce its ability to lower serum Li concentrations; and 4) even when administered after peak serum Li concentrations had been achieved, a single dose of SPS was effective in lowering serum Li levels. CONCLUSIONS: SPS may be efficacious in the treatment for Li toxicity under certain circumstances, even when there is delay to treatment. Additional study is warranted to further characterize the ability of SPS to alter Li kinetics.

L-tyrosine potentiation of opioid-induced analgesia utilizing the hot-plate test.

The effects of L-tyrosine (L-TYR) on the analgesic activity of several opioids were determined utilizing a hot-plate test. L-TYR (200 mg/kg) significantly potentiated (P < .05) the analgesic activity of morphine sulfate (10 mg/kg) and codeine sulfate (30 mg/kg). The opioid-induced analgesia and its potentiation by L-TYR was abolished by naloxone pretreatment. Increasing the dose of L-TYR (25-200 mg/kg) resulted in a dose-dependent potentiation of morphine-induced analgesia. The observed potentiation was positively correlated with increases in brain TYR concentrations; blockade of L-TYR uptake into the brain by the coadministration of L-valine attenuated this potentiation. With the exception of L-tryptophan, all other L-amino acids, as well as D-TYR, failed to mimic the potentiating action of L-TYR. As determined by alpha-methyl-p-TYR pretreatment, the L-TYR-induced potentiation was dependent upon increased catecholamine synthesis. These results demonstrate that L-TYR dose dependently potentiates the analgesic activity of opioids and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response.

Comparison between phenylpropanolamine and structurally related compounds on gastric transit in the rat.

Our laboratory previously reported several pharmacological differences between phenylpropanolamine [PPA; (+/-)-norephedrine] and its structurally related compounds in regard to their activity on cardiovascular and appetite-suppressant parameters. The present study investigates the pharmacological differences between PPA, [1R,2R]-(-)-norephedrine [(-)-NOR], [1S,2S]-(+)-norephedrine [(+)-NOR], [1R,2S]-(-)-ephedrine [(-)-EPH], [1S,2R]-(+)-ephedrine [(+)-EPH], [1R,2S]-(-)-norpseudoephedrine [(-)-NORP], [1S,2R]-(+)-norpseudoephedrine [(+)-NORP], [1R,2R]-(-)-pseudoephedrine [(-)-PSE], and [1S,2S]-(+)-pseudoephedrine [(+)-PSE], as determined by their ability to inhibit gastric transit in the rat. (-)-Norephedrine was approximately three times more potent in inhibiting gastric transit than (+)-NOR (p < 0.01). As anticipated, the racemic mixture, PPA, demonstrated an ED50 (25.1 mg/kg) of approximately the mean of the ED50s from the component enantiomers (14.7 and 47.0 mg/kg, respectively). Similarly, administration of 20 mg/kg of either (-)-EPH, (+)-EPH, (-)-PSE, or (+)-PSE significantly decreased gastric transit by 26% (p < 0.001), 12% (p < 0.01), 10% (p < 0.01), and 11% (p < 0.01), respectively. Administration of (-)-NORP and (+)-NORP were without effect. These data confirm and extend previous findings demonstrating pharmacological differences between PPA and its structurally related compounds.

Cholestyramine as an adsorbent in acute lindane poisoning: a murine model.

STUDY OBJECTIVES: To compare the effectiveness of single-dose cholestyramine versus single-dose activated charcoal in preventing clinical toxicity after acute lindane ingestion. DESIGN: CD-1 mice received lindane by enteral (gavage) and parenteral (intraperitoneal) routes, followed by enteral administration of either cholestyramine (2.25 g/kg) or activated charcoal (2.25 g/kg), with subsequent observation for convulsions and death. MEASUREMENTS: The doses of lindane at which 50% of mice developed convulsions (CD50) and at which 50% of mice died (LD50) were established and compared among control, charcoal-, and cholestyramine-treated groups. RESULTS: For lindane administered by gavage, the differences in the CD50 and LD50 between the control and the activated charcoal groups were not statistically significant. However, a significant difference did exist in both the CD50 and the LD50 between the group receiving cholestyramine and the control group and between the cholestyramine and activated charcoal groups. After IP administration of lindane, the difference in CD50 or LD50 among control, activated charcoal, or cholestyramine groups was not significantly different. CONCLUSION: In the murine model, cholestyramine is more effective than activated charcoal in preventing absorption of lindane, thus preventing convulsions and death. These data support the need for clinical studies to determine whether cholestyramine may be a more effective treatment than activated charcoal for acute lindane ingestions in human beings.

Effect of phenylpropanolamine and related compounds on beta-adrenoceptor-induced activation of adenylyl cyclase.

While oral administration of therapeutic doses of phenylpropanolamine (PPA) does little to cardiovascular function in humans, intravenous doses administered to experimental animals are known to alter heart rate and blood pressure. Previous in vivo and in vitro studies have documented a beta-adrenoceptor agonist action for PPA and thus it was of interest to investigate whether these effects could be partially mediated by a direct interaction with beta-adrenoceptors. Phenylpropanolamine, [1R, 2R]-(-)-norephedrine, [1S, 2S]-(+)-norephedrine, [1S, 2R]-(+)-norpseudoephedrine, [S]-(+)-amphetamine, and [1R, 2S]-(-)-ephedrine, were compared with the known beta-adrenoceptor agonists [R]-(-)-epinephrine (EPI), [R]-(-)-norepinephrine (NE), and [R*, S*]-(+/-)-isoproterenol (ISO) for their ability to increase the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cAMP) in minces of rat heart. Of the compounds investigated only NE, EPI, and ISO, as well as, forskolin, which directly stimulates adenylyl cyclase, significantly (p < 0.05) increased intracellular levels of cAMP. The other phenethylamines were without effect. The results of this study demonstrate that PPA and its diastereomers do not act directly at beta-adrenoceptors to alter cardiac function and supports the hypothesis that significant agonist activity of beta-phenethylamines at the beta-adrenoceptor requires phenolic/aryl ether substitution on the phenyl-ring (typically positions 3, 4 and/or 5).

Effects of L-tyrosine on mixed-acting sympathomimetic-induced pressor actions.

We previously reported the ability of L-tyrosine (L-TYR) to potentiate the anorectic activity of various mixed-acting sympathomimetics including [R*S*]-(+/-)-norephedrine [phenylpropanolamine (PPA)], [1R,2S]-(-)-ephedrine (EPH), and [S]-(+)-amphetamine (AMPH) in hyperphagic rats. Included in those studies was the attenuation of L-TYR's effect when coadministered with L-valine, a large neutral amino acid that competes with L-TYR for uptake into the brain, suggesting a central locus for the action of L-TYR. Additional studies demonstrated the inability of L-TYR to alter the peripherally mediated PPA-, EPH-, and AMPH-induced increases in gastrointestinal transit time and retention and intrascapular brown adipose tissue thermogenesis. Because the mixed-acting sympathomimetics are known to increase blood pressure, these studies examined the ability of L-TYR to influence the pressor responses to PPA, EPH, and AMPH (0.03-1 mg/kg) in urethane-anesthetized rats. Each of the mixed-acting sympathomimetics significantly increased mean arterial, systolic, and diastolic blood pressures when administered alone, but no potentiation by L-TYR was observed. These results demonstrate the inability of L-TYR to potentiate the peripheral vasopressor effects of PPA, EPH, and AMPH. These data, in conjunction with our previous findings, suggest that the potentiation by L-TYR of the mixed-acting sympathomimetics is largely restricted to centrally mediated responses.

L-tyrosine fails to potentiate several peripheral actions of the sympathomimetics.

We have recently reported the ability of L-tyrosine (L-TYR) to potentiate the anorectic activity of various mixed-acting sympathomimetics including phenylpropanolamine (PPA), l-ephedrine (EPH) and d-amphetamine (AMP). Included in those studies was the attenuation of L-TYR's effect when coadministered with L-valine, a large neutral amino acid which competes with L-TYR for uptake into the brain, suggesting a central locus for the action of L-TYR. To determine to what extent L-TYR can potentiate peripheral actions, we investigated the effects of L-TYR with either PPA (20 mg/kg), EPH (20 mg/kg) or AMP (1.75 mg/kg) on gastric transit, gastric retention and intrascapular brown adipose tissue thermogenesis. In each of the paradigms studied, PPA, EPH and AMP significantly increased the expected sympathomimetic-mediated response, but no potentiation of L-TYR was observed. These results are consistent with the hypothesis that L-TYR potentiates the anorectic activity of the mixed-acting sympathomimetics largely via an action at a central locus.

L-tyrosine potentiates the anorexia induced by mixed-acting sympathomimetic drugs in hyperphagic rats.

The effects of L-tyrosine (L-TYR) on the anorectic activity of several mixed-acting sympathomimetics were determined during the dark cycle in rats made hyperphagic by food deprivation. L-TYR (200 mg/kg) significantly potentiated the anorectic activity of phenylpropanolamine, (-)-ephedrine and (+)-amphetamine by 48, 50 and 37%, respectively. When the dose of L-TYR was varied (25-400 mg/kg), a significant dose-dependent relationship was noted. The observed potentiation was positively correlated with increases in brain TYR concentrations; blockade of L-TYR uptake into the brain by the coadministration of L-valine prevented this potentiation. Various other L-amino acids, as well as D-TYR, failed to mimic the potentiating action of L-TYR. As determined by alpha-methyl-p-TYR pretreatment, the L-TYR-induced potentiation was dependent upon increased catecholamine synthesis. Although various other mixed-acting sympathomimetic anorexiants were similarly potentiated by L-TYR, the direct-acting beta-2 adrenoceptor anorexiants, salbutamol and methoxyphenamine, were not. These results indicate that L-TYR specifically potentiates the anorectic activity of the studied mixed-acting sympathomimetics and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response. The possibility that the effect of mixed-acting sympathomimetics is normally limited by the availability of L-TYR is suggested.