Update on treatment of lysosomal storage diseases.

Lysosomal storage diseases (LSDs) are a large group of disorders caused by a deficiency of specific enzymes responsible for the degradation of substances present in lysosomes. In the past few years, treatments for LSDs were non specific and could only cope with signs and symptoms of the diseases. A successful therapeutic approach to LSDs should instead address to the underlying causes of the diseases, thus helping the degradation of the accumulated metabolites in the various organs, and at the same time preventing their further deposition. One way is to see to an available source of the deficient enzyme: bone marrow transplantation, enzyme replacement therapy and gene therapy are based on this rationale. The purpose of substrate reduction therapy is to down regulate the formation of the lysosomal substance to a rate at which the residual enzyme activity can catabolize the stored and de novo produced lysosomal substrate. Chemical chaperone therapy is based on small molecules able to bind and stabilize the misfolded enzymes. This paper offers a historical overview on the therapeutic strategies for LSDs.

Sevelamer hydrochloride (Renagel), a nonabsorbed phosphate-binding polymer, does not interfere with digoxin or warfarin pharmacokinetics.

Sevelamer hydrochloride (Renagel) is a nonabsorbed phosphate-binding polymer marketed for the treatment of hyperphosphatemia in adult patients receiving hemodialysis. Sevelamer also exhibits bile acid-binding properties resulting in LDL cholesterol lowering. Potential drug interactions between digoxin and warfarin and sevelamer were studied. These two drugs were chosen because they are known to bind to the bile acid-binding polymers, cholestyramine and colestipol. Studies were single dose, crossover, with or without six 2.4 g doses of sevelamer. Plasma concentrations were determined using validated analytical methods. The pharmacokinetic profiles of digoxin and warfarin were not altered by the simultaneous and continued administration of sevelamer. Values for the ratio of ln[AUC(0-infinity)], ln[AUC(0-t)], and ln[Cmax] with and without sevelamer were close to 100%, and the 90% confidence intervals for these ratios were within the 80% to 125% range. It was concluded that sevelamer does not interfere with the absorption or excretion of digoxin or warfarin.

Sevelamer hydrochloride (Renagel), a phosphate-binding polymer, does not alter the pharmacokinetics of two commonly used antihypertensives in healthy volunteers.

Sevelamer hydrochloride (Renagel) is a nonabsorbed phosphate-binding polymer approved for the treatment of hyperphosphatemia in adult hemodialysis patients. The authors studied the potential effect of sevelamer on the pharmacokinetics of two antihypertensive drugs, enalapril (20 mg) and metoprolol (100 mg), commonly used in end-stage renal disease patients. Two studies were conducted. Both were single dose, crossover design with or without a 2.4 g dose of sevelamer in healthy volunteers. Within each study, there was a 7-day washout interval between the two dose administrations. There were 28 volunteers in the enalapril study and 32 in the metoprolol study. The mean plasma concentrations versus time profiles of enalapril, enalaprilat, and metoprolol were not altered by the simultaneous administration of sevelamer. Values for the ratio of ln[AUC(0-infinity)], ln[AUC(0-t)], and ln(Cmax] with and without sevelamer were approximately 100%, and the 90% confidence intervals for the ratios of these parameters with and without sevelamer were within the 80% to 125% range in all cases except for the ln[Cmax] of enalapril, which had an upper confidence bound of 125.4%. The authors conclude that sevelamer does not interfere with the absorption and elimination of enalapril and metoprolol.

Use of recombinant human thyrotropin before radioiodine therapy in patients with advanced differentiated thyroid carcinoma.

The use of 131I for radioablative therapy in patients with differentiated thyroid cancer (DTC) requires a sufficient serum concentration of TSH for efficient thyroid tissue uptake of iodine. We describe the use of recombinant human TSH (rhTSH) in conjunction with ablative radioiodine therapy (RIT) in 11 patients (16 total treatments) with advanced and/or recurrent DTC (5 papillary, 6 follicular) for whom withdrawal of thyroid hormone suppression therapy (THST), the standard method to increase serum TSH, was not an option. Indications for rhTSH use in these patients included inability to tolerate withdrawal of thyroid hormones due to very poor physical condition or inability to achieve sufficient serum TSH levels after THST withdrawal. Ten patients had undergone thyroidectomy, and most (9 of 11) had received prior ablative RIT after THST withdrawal. Baseline thyroglobulin levels ranged from 25 to nearly 30,000 ng/mL, reflecting the heterogeneity of the patient population. In 7 cases (5 patients), posttherapy thyroglobulin levels assessed at a mean of 4.3 months (range, 2-10 months) after 131I therapy were decreased by at least 30% compared to pretherapy levels. In follow-up visits, an additional 3 patients showed marked clinical improvement or decreased or stabilized tumor burden in whole body scans compared to pretherapy scans. Three patients died of progressive disease within 2 months of therapy before follow-up assessments occurred. No adverse events were reported among the 8 surviving patients. The results suggest that rhTSH offers a promising alternative to THST withdrawal to allow ablative RIT after effective TSH stimulation in patients with advanced recurrent DTC who would not otherwise be able to receive this treatment. This therapeutic indication extends the clinical potential of this new agent, already demonstrated to be effective for use with 131I for diagnostic purposes.

Bacteria isolated from rock art paintings: the case of Atlanterra shelter (south Spain).

The Sierra de la Plata is an Aljibe yellow sandstone formation from the Acheulian period. There are a few shelters, some of them with rock art paintings. The most representative one, and subjected to anthropogenic pressure, is that of Atlanterra, situated in a residential area. This shelter contains some rock art paintings made with iron oxides. The bacteria present in these paintings were isolated and identified using an automatic method: fatty acid methyl esters profiling. Most of the bacteria belong to the Bacillus genus, B. megaterium being the most abundant species. The isolated strains are able to reduce hematite. This is significant due to the fact that Fe(III)-(hydr)oxides are the most abundant pigments in rock art.

Recombinant human thyroid-stimulating hormone (rhTSH): clinical development.

Recombinant human thyroid-stimulating hormone (rhTSH) was developed to safely provide exogenous TSH stimulation in patients on thyroid hormone suppression therapy (THST), which is integral to long-term management of well-differentiated thyroid cancer. Such stimulation allows detection of thyroid remnant and neoplastic tissue by serum thyroglobulin (Tg) testing and/or diagnostic iodine-131 (I-131) imaging, sparing patients THST withdrawal and resultant metabolic impairment, discomfort and morbidity needed to obtain endogenous TSH stimulation. An extensive clinical development process including nearly a decade of multinational, multicentre study or other follow-up of over 500 patients has demonstrated that: 1) rhTSH is safe and well-tolerated, with the main side effects transient, mild to moderate nausea in approximately 11% or headache in approximately 7% of patients. Of note, no antibodies to TSH were detected in any patient, even in 27 patients who have received multiple treatments; 2) in patients on THST, rhTSH effectively provides TSH stimulation that allows I-131 diagnostic imaging to detect persistent or recurrent disease with a generally equivalent sensitivity and image quality to those observed after THST withdrawal; 3) rhTSH increases the sensitivity of Tg testing in patients on THST; 4) rhTSH administration allows patients to remain euthyroid and obviates THST withdrawal; therefore, rhTSH administration avoids the significantly lower quality of life and greater discomfort and morbidity due to hypothyroidism during withdrawal, according to patients' and caregivers' ratings on validated instruments. These safety and efficacy findings have led to regulatory approval of rhTSH for diagnostic use in the United States in December 1998; regulatory approval is pending in the European Union.

The role of recombinant thyroid-stimulating hormone (rhTSH) in the detection and management of well-differentiated thyroid carcinoma: a roundtable discussion.

A Roundtable meeting of European endocrinologists and nuclear medicine physicians recently examined the role of recombinant human thyroid-stimulating hormone (rhTSH, Thyrogen, thyrotropin alfa, Genzyme Corporation, Cambridge, MA, USA) in the detection and management of well-differentiated thyroid carcinoma. The meeting sought to review clinical work to date and to provide guidance and perspective on the agent's application in everyday practice. The Roundtable included a panel discussion centering on three major topics: 1) rationale for use of exogenous versus endogenous TSH stimulation of radioiodine uptake and thyroglobulin (Tg) production; 2) impact and use of rhTSH in diagnostic follow-up; and 3) role of rhTSH in radioablation. The panel concluded that obtaining TSH stimulation of radioiodine uptake and Tg production exogenously with rhTSH obviates the weeks-long withdrawal from thyroid hormone suppression therapy (THST) needed to obtain such stimulation endogenously. rhTSH administration thereby eliminates morbidity, discomfort and uncertainties of compliance and timing associated with THST withdrawal. Thus compared to withdrawal, rhTSH administration offers important advantages in safety, quality of life, reliability, predictability and convenience to patients and care providers. rhTSH therefore represents a major advance in the diagnostic follow-up of well-differentiated thyroid cancer. By increasing the sensitivity of serum Tg testing during THST, rhTSH administration also improves the sensitivity of diagnostic follow-up. In addition, heightening the sensitivity of Tg testing may permit more selective application of iodine-131 whole body scanning, decreasing the invasiveness of diagnostic follow-up. Clinical studies are underway to confirm the preliminary promise of rhTSH as an adjunct to radioablation of normal or neoplastic thyroid tissue, with emphasis on the therapeutic setting.

Bacteriological indicators of faecal contamination: result of a loading experiment with untreated urban wastewater.

Some observations were made on the behaviour of total coliforms, faecal coliforms, enterococci, numbers of aerobic bacteria, salmonellas and sulphur-reducing clostridia as bacterial indicators of faecal contamination of groundwater. A controlled irrigation experiment was carried out with untreated residual water in the alluvial aquifer of the Vega of Granada (Spain). The results obtained confirm the value of these parameters are useful indicators of very recent faecal contamination; and changes were detected as the level of the freatic layer increased and the chemical composition of the groundwater changed. These groups of micro-organisms persisted for about 200 h, with the exception of the aerobes which survived for much longer. Salmonellas were present at levels too low to calculate the extent of faecal contamination and sulphur-reducing clostridia were not detected. The results obtained show that irrigation with untreated wastewater offers a lower risk of microbiological contamination of groundwater compared with the direct addition of waters decanted and/or previously filtered.