[New drugs; pegaptanib and ranibizumab]. / Nieuwe geneesmiddelen; pegaptanib en ranibizumab.

The neovascular ('wet') form of age-related macular degeneration (AMD) is characterized by vascular growth and leakage in the retina. Two new drugs, pegaptanib and ranibizumab, have been shown to improve vision or slow the progression of AMD. Both drugs inhibit the action of vascular endothelial growth factor--pegaptanib as an oligonucleotide and ranibizumab as a monoclonal antibody--thereby decreasing angiogenesis in the eye. Adverse effects are associated with the intravitreal administration of both drugs and include increased intraocular pressure, local bleeding, and infection.

[New drugs; exenatide and sitagliptin]. / Nieuwe geneesmiddelen; exenatide en sitagliptine.

Incretin hormones, secreted upon food intake, play an important role in the regulation of blood glucose levels. In type 2 diabetes mellitus, the incretin response is decreased. Substitution of incretin is a novel pharmacological target which restores postprandial glucose homeostasis. Exenatide is a mimetic of the incretin glucagon-like peptide-I (GLP-I). Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4), which breaks down GLP-I. Both drugs increase the GLP-I concentration, thereby improving insulin secretion from pancreatic p cells, restoring glycaemic control, preventing beta cell destruction, delaying gastric emptying, and reducing food intake.

[New drugs; natalizumab]. / Nieuwe geneesmiddelen; natalizumab.

The drug natalizumab represents a new pharmacological approach in the treatment ofvery active relapsing-remitting multiple sclerosis (MS). It is a humanised murine monoclonal antibody and binds to an integrin on the surface oflymphocytes, thereby preventing them from transmigrating across the endothelium and causing inflammation in the nervous tissue. The drug has been shown to decrease the occurrence of relapses and progression of MS. A few severe adverse effects (such as the viral progressive multifocal leuko-encephalopathy) have been reported, and its clinical and long-term effects are not fully known at present. Therefore, further research is required to determine the role of natalizumab in clinical practice.

[New drugs; rimonabant]. / Nieuwe geneesmiddelen; rimonabant.

The endocannabinoid system controls the regulation of food intake and appetite in the brain and lipogenesis in adipose tissue. Rimonabant belongs to the new drug class of cannabinoid-1 receptor antagonists. It can decrease appetite and food intake and thus stimulate weight loss. Rimonabant is indicated for severe obesity and as an adjunct to lifestyle modifications for obese patients with type 2 diabetes or hyperlipidaemia. Safety concerns limit the clinical applicability of the drug. The drug has not been approved in the US due to its neurological and psychiatric adverse effects. Rimonabant is approved in Europe but is contraindicated in patients with major depression and those taking antidepressants.

[New drugs; sunitinib and sorafenib]. / Nieuwe geneesmiddelen; sunitinib en sorafenib.

Sunitinib and sorafenib are both indicated for the treatment of advanced kidney carcinoma of the 'clear cell' type after failure of, or resistance to, other treatments. Both drugs inhibit the tyrosine-kinase activity of a number of growth factor receptors; sorafenib has an additional inhibitory effect on serine/threonine-kinase activity. This mechanism decreases signal transduction and results in an inhibition of tumour cell growth and angiogenesis. The adverse effects of the two drugs are different: sunitinib causes mainly fatigue and gastrointestinal discomfort, whereas sorafenib's most frequent adverse effects are diarrhoea, rash, the palmar-plantar erythrodysaesthesia syndrome, and hypertension.

[New drugs; varenicline]. / Nieuwe geneesmiddelen; varenicline.

Nicotine acts in the brain by releasing dopamine in the mesolimbic pathway which results in a reward effect and in dependence when used chronically. The effect of nicotine is mediated via nicotinergic acetylcholine receptors of the alpha4beta2 subtype ofwhich varenicline is a partial agonist. Varenicline can be used for quitting smoking because of two mechanisms: it acts as a partial agonist and thus reduces the symptoms of craving when quitting smoking, and it has antagonistic actions by binding the receptor instead of nicotine and therefore decreases the reward effect of nicotine. The most important side effects of varenicline are nausea, vomiting and headache. After one year, 22% of the treated group continued to abstain from smoking.

[New drugs; daptomycin]. / Nieuwe geneesmiddelen; daptomycine.

Being a cyclic lipopeptide, daptomycin belongs to a new class of antibiotics. It acts by forming a pore in the bacterial membrane thus causing leakage of potassium and subsequent depolarization and arrest of cell function. Daptomycin has a bactericidal action on Gram-positive bacteria and is registered for the treatment of adults with complicated skin and soft tissue infections caused by Gram-positive microorganisms. There is limited experience with treatment of Staphylococcus aureus bacteraemia. Its main adverse effects include gastrointestinal symptoms, skin reactions at the site of infusion, and raised serum creatine kinase.

[New drugs; nitisinone]. / Nieuwe geneesmiddelen; nitisinon.

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase (4HPPD). Its rare area of use is hereditary tyrosinaemia, a life-threatening disease in which the last step in the catabolism of tyrosine cannot be taken due to the absence of an enzyme. The inhibition of 4HPPD, an enzyme that is active early in the catabolic cascade, prevents the accumulation of toxic metabolites of tyrosine.

[New medications; ziconotide]. / Nieuwe geneesmiddelen; ziconotide.

Ziconotide is a synthetic analogue of a peptide found in the poison of the marine snail Conus magus. Ziconotide blocks N-type calcium channels, which play an important role in the transmission of pain signals in the dorsal ganglia of the spinal cord. The drug is indicated for 'severe chronic pain' and is administered intrathecally.

[New medications; zonisamide]. / Nieuwe geneesmiddelen; zonisamide.

Zonisamide is an adjuvant for the treatment of patients with partial epilepsy, with or without secondary generalisation. It affects, among other things, the voltage-sensitive sodium and calcium channels, thus disrupting synchronised neuronal firing; as a result, it diminishes the spread of seizure discharges.

[New drugs; ivabradine]. / Nieuwe geneesmiddelen; ivabradine.

Ivabradine lowers the heart rate by inhibiting the cardiac pacemaker current that is responsible for diastolic depolarisation. The most important side effect is the appearance of light flashes (phosphenes). The agent can be used in patients with angina pectoris when beta-blockers are insufficiently effective, provided that the heart rate is at least 60 beats per minute at the beginning of the treatment.

[New medications; bevacizumab]. / Nieuwe geneesmiddelen; bevacizumab.

Bevacizumab is a humanised monoclonal antibody that targets vascular endothelial growth factor. By blocking the growth factor, bevacizumab inhibits the development of new blood vessels, which in turn inhibits the growth oftumours and metastases. Mean disease-free survival is prolonged in patients with metastatic colorectal carcinoma who are treated with bevacizumab. Evaluation of bevacizumab in other indications is underway.

[New drugs; palifermin]. / Nieuwe geneesmiddelen; palifermine.

Palifermin is a human keratinocyte growth factor that is produced in Escherichia coli by recombinant-DNA-technology. This substance protects against oral mucositis in adults undergoing myeloablative therapy. The safety of this product--being a growth factor --in the long term has not yet been shown. Adverse effects may occur in the skin and mucous membranes.

[New medications; erlotinib]. / Nieuwe geneesmiddelen; erlotinib.

Erlotinib inhibits the phosphorylation of the epidermal growth-factor receptor (EGFR/HERI), a tyrosinekinase protein. This results in an inhibition of signal transduction and therefore decreased cell division and increased cell death. The agent is indicated for the treatment of patients with advanced local or metastasised non-small-cell pulmonary carcinoma after other cytostatic therapy has failed.

[New drugs; omalizumab]. / Nieuwe geneesmiddelen; omalizumab.

Omalizumab is a humanised monoclonal antibody that binds to circulating IgE, inhibiting its binding to the surface of mast cells and basophilic granulocytes. This prevents the release of pro-inflammatory mediators that produce an allergic response. This targeted mechanism of action provides a novel therapeutic approach for the treatment of patients with severe persistent, therapy-resistant allergic asthma. Omalizumab is administered subcutaneously in addition to other anti-asthma therapy. Until recently, the most important side effects are skin reactions at the site of administration and headache. Prospective data on additional long-term side effects are still being collected.

Distinct subpopulations of elicited human macrophages in peritoneal dialysis patients and women undergoing laparoscopy: a study on peroxidatic activity.

The endogenous peroxidatic activity (PA) pattern of peritoneal macrophages from 24 continuous ambulatory peritoneal dialysis (CAPD) patients and from five healthy women undergoing laparoscopy was studied. In general, the macrophages showed two different PA patterns in vivo: exudate and negative macrophages. However, two of 24 CAPD patients showed resident macrophages, the first described in vivo in man. Since, in general, the examined human peritoneal macrophages are exudate and PA-negative, this suggests, in accordance with the animal model system, that a chronic sterile inflammation exists in the peritoneal cavity of CAPD patients and healthy women undergoing laparoscopy. After 2 hr culture, blood monocytes and peritoneal macrophages transformed into cells with the characteristics of exudate-resident and resident macrophages, so isolation procedures that include short periods of culture can change the developmental stage of human monocytes and macrophages.

Islet cell hormone release immediately after human pancreatic transplantation. A marker of tissue damage associated with cold ischemia.

Pancreatic graft procurement, preservation, and transplantation surgery may result in damage to and loss of the integrity of endocrine cells and consequently in leakage of cell products into the insular vascular capillaries. Thus, the amount of alpha-, beta-, and pancreatic polypeptide (PP) cell products released into the vascular space of the recipient immediately after graft reperfusion may reflect islet cell injury. To test this hypothesis, we assessed glucagon, PP, C-peptide, and insulin levels in a prospective study of 22 consecutive renal-pancreatic transplantations. Transplantation-related parameters were used to account for differences in hormone release. Five grafts were preserved using Euro-Collins preservation fluid and 17 grafts were preserved using University of Wisconsin solution (UW). The first sign of a reinstalled physiological axis was the decrease of the blood glucose concentration after a median duration of 40 min (range 5-90 min) and the association of the recipient's ambient blood glucose levels with insulin release between 25 and 180 min after reperfusion. The delay period before a fall in blood glucose was observed correlated with cold ischemia time (rs = 0.73, P < 0.001, n = 21). An immediate and marked increase in plasma levels of glucagon (from 180 +/- 18 to 585 +/- 99 ng/L, mean +/- SEM), PP (from 57 +/- 8 to 122 +/- 13 pmol/L), C-peptide (from < 0.06 +/- 0.02 to 5.43 +/- 0.63 nmol/L), and insulin (from 0.15 +/- 0.21 to 2.05 +/- 0.26 nmol/L) was observed. C-peptide release correlated with glucagon (r = 0.76, P < 0.001) and PP (r = 0.60, P < 0.01). The hormone release was compared with computed tomography scans that were performed in the immediate postoperative period in 15 UW-preserved allografts. The diameter of the pancreatic head was increased and ranged from 4.5 to 7.7 cm (mean 6.2 cm). Peroperative C-peptide release significantly correlated with morphological graft changes reflected by the pancreatic head diameter (r = 0.58, P = 0.02). In a stepwise multiple regression analysis, cold ischemia time was a significant factor for the release of PP (r2 = 0.18, P = 0.049) and C-peptide (r2 = 0.35, P = 0.004). We suggest that peroperative hormone release reflects endocrine tissue damage. Furthermore, cold ischemia time may jeopardize the pancreatic allograft after relatively short preservation times, even when UW is used.

Long-term use of magnesium hydroxide as a phosphate binder in patients on hemodialysis.

The long-term use of magnesium hydroxide [Mg(OH)2] as a phosphate binder was investigated in 18 patients on chronic hemodialysis. All patients received a basal treatment with oral calcium carbonate. Vitamin D supplements were not used. In period I each patient ingested aluminum hydroxide [Al(OH)3], in period II Mg(OH)2 and in period III Mg(OH)2 and Al(OH)3 together. During period II and III a dialysate devoid of Mg was used. Mg(OH)2 doses were adjusted to prevent severe hypermagnesemia and diarrhea. The mean dose of Mg(OH)2 in period II was 2.4 +/- 0.6 and in period III 2.6 +/- 1.2 g/day. Serum phosphate increased significantly in period II and fell again in period III. Despite a halving of the Al(OH)3 dose in period III, serum Al was similar in period I and period III (55.8 +/- 19.1 vs 57.1 +/- 27.3 microg/l). Parathyroid hormone (PTH) concentration fell in period II and decreased even further in period III. We conclude that oral Mg(OH)2 may reduce the required Al(OH)3 dose, however, without an effect on serum Al concentration. The observed suppression of parathyroid activity needs further study.

Light chain deposition disease without detectable light chains in serum or urine. Report of a case and review of the literature.

A patient presenting with a nephrotic syndrome and chronic renal failure caused by light chain deposition disease (LCDD) without detectable light chains in serum and urine is presented. Only a few patients with LCDD but without detectable light chains in serum and urine have hitherto been reported. The diagnosis was made by light-microscopic and immunofluorescent examination of a percutaneous renal biopsy. The histological differential diagnosis of LCDD includes diabetic glomerulosclerosis, renal amyloidosis and membranoproliferative glomerulonephritis. For the histological diagnosis of LCDD, immunofluorescence using anti-kappa and anti-lambda antisera is essential. Although renal involvement is a constant feature in LCDD, other sites of deposition of light chains have been reported. The absence of detectable light chains in serum or urine is discussed.

Simultaneous pancreas and kidney transplantation: a feasible procedure in selected patients.

We analyzed the overall results of 24 simultaneous pancreas and kidney transplantations (SPK), performed in our hospital between April 1986 and June 1990. All patients had type I diabetes mellitus and end-stage renal failure. We used bladder drainage of the pancreatic exocrine secretions through a duodenocystostomy. The blood vessels of both grafts were anastomosed to the iliac vessels. The immunosuppressive management was triple-therapy with cyclosporin, azathioprine and prednisone. All organs were transplanted without matching donors and recipients for HLA. At the time of transplantation, mean recipient age was 37 yr; the average duration of diabetes was 22 yr. After disappointing results in the first 4 patients, the pancreas was placed intraperitoneally instead of extraperitoneally and the antibiotic drug regimen was altered. In the second group (n = 20), patient survival was 100%; 1-yr pancreas and kidney graft survival were 65 and 62%, respectively. Duration of hospitalization and pancreas and kidney graft loss were positively correlated with the number of rejection episodes. After 1 yr of follow-up, the mean creatinine clearance was 62 ml/min and the mean HbA1c was 5.5%. Blood glucose levels and oral glucose tolerance tests were also normal. We conclude that patient and graft survival after SPK are satisfactory, although rejection-related morbidity is still a major problem.