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Biomedical subjects

P M Hooymans

Publications and source records attributed to P M Hooymans.

At least 19 recordsLinked to original sources
PubMed2006

Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?

BACKGROUND: 6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology. AIMS: Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients. PATIENTS AND METHODS: Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging. RESULTS: Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia. DISCUSSION: Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine. CONCLUSION: 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.

Adult↗
PubMed2006

Review article: thiopurines in inflammatory bowel disease.

BACKGROUND: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. AIM: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. METHODS: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. RESULTS: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. CONCLUSIONS: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.

Azathioprine↗
PubMed2006

Pancytopenia due to high 6-methylmercaptopurine levels in a 6-mercaptopurine treated patient with Crohn's disease.

In a 23-year-old female with colonic Crohn's disease 6-mercaptopurine 100 mg daily (1.7 mg/kg) was added to mesalamine and prednisolone therapy because of ongoing disease activity. One month later she had fever and a pancytopenia. 6-methylmercaptopurine ribonucleotides levels were extremely elevated (57,000 pmol/8x10(8) red blood cells) and 6-thioguanine nucleotides levels were subtherapeutically (126 pmol/8x10(8) red blood cells). Genotyping showed a wildtype thiopurine S-methyltransferase TPMT(H/H) (*1/*1) genotype and a wildtype inosine triphosphate pyrophosphatase gene. TPMT and inosine triphosphate pyrophosphatase activity were normal. The pancytopenia recovered spontaneously within a few weeks, parallel with decreasing 6-methylmercaptopurine ribonucleotides levels after interrupting 6-mercaptopurine treatment. Epstein-Barrvirus, Cytomegalovirus and Herpesvirus infections were excluded by serology. This is the first report of pancytopenia due to extremely high 6-methylmercaptopurine ribonucleotides levels. No relation was found with the genotype of TPMT and inosine triphosphate pyrophosphatase enzymes, which play key roles in the thiopurine metabolic pathway. Apparently, 6-methylmercaptopurine ribonucleotides metabolites can cause pancytopenia, as was already known for 6-thioguanine nucleotides.

Adult↗
PubMed2005

The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients.

BACKGROUND: In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S-methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6-methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites. AIM: To examine the in vivo pharmacokinetic interaction between mesalazine and mercaptopurine. METHODS: A prospective study was performed in quiescent inflammatory bowel disease patients using the combination of mercaptopurine and mesalazine. Laboratory parameters, 6-methylmercaptopurine ribonucleotide and tioguanine levels and thiopurine S-methyltransferase activity in erythrocytes were measured at stable medication, after mesalazine discontinuation and mesalazine reintroduction, further mercaptopurine was continued. RESULTS: Seventeen patients were participated. Mean mercaptopurine dose was 0.78 mg/kg/day and median of mesalazine dose was 3000 mg/day. After mesalazine discontinuation, mean tioguanine levels changed significantly from 262 to 209 pmol/8 x 10(8) red blood cell, increasing to 270 after reintroduction. Mean 6-methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 x 10(8) red blood cell respectively. Mean 6-methylmercaptopurine ribonucleotide/tioguanine ratio increased significantly from 6.3 at baseline to 11.2. Mean baseline thiopurine S-methyltransferase activity was 0.58 pmol/10(6) red blood cell/h and stable. All patients had wild-type thiopurine S-methyltransferase genotypes however, leucocyte counts were stable. DISCUSSION: A significantly higher tioguanine levels and improving 6-methylmercaptopurine ribonucleotide/tioguanine ratio were found during mesalazine/mercaptopurine combination. Theoretically, mesalazine inhibits thiopurine S-methyltransferase activity. In vivo thiopurine S-methyltransferase activity did not change, however. CONCLUSION: Mesalazine has synergistic effects on mercaptopurine therapy, but the mechanism is unclear. Combining these drugs may be further indication for mesalazine in inflammatory bowel disease treatment.

Adult↗
PubMed2003

Safety of thiopurines in the treatment of inflammatory bowel disease.

BACKGROUND: Thiopurines have proven efficacy in inflammatory bowel disease. However, concerns regarding toxicity have limited the use of these agents as first line of medical therapy. METHODS: Review of the literature regarding metabolism, efficacy and side effects. RESULTS: In clinical trials, up to 15% of patients discontinued 6-mercaptopurine or its pro-drug azathioprine prematurely due to adverse events. These events may be divided into dose-independent idiosyncratic reactions and dose-related, pharmacologically explainable toxicity. Dose-independent reactions include skin rash, fever, diarrhoea and pancreatitis. Most frequently observed dose-dependent adverse events are nausea, malaise and myelotoxicity. Furthermore, dose-dependent and dose-independent hepatotoxicity may occur. Recent insights obtained by therapeutic drug monitoring in patients on azathioprine or 6-mercaptopurine have led to strategies to reduce toxicity. One strategy is to detect poor metabolisers of thiopurines by establishing the activity of the key enzyme thiopurine methyltransferase. However, the clinical relevance of this strategy is still a point of debate. Another strategy is to administer 6-thioguanine, which is an agent close to the effective 6-thioguanine nucleotides. CONCLUSION: Therapeutic drug monitoring of thiopurines resulted in strategies to reduce toxicity. The value of these strategies has yet to be proven in prospective randomized trials.

Azathioprine↗
PubMed2002

Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study.

Drugs which directly counteract nitric oxide (NO), such as endothelial receptor blockers, NO-synthase inhibitors, and NO-scavengers, may be effective in the acute treatment of migraine, but are also likely to be effective in migraine prophylaxis. In the underlying pilot study the prophylactic effect of the NO scavenger hydroxocobalamin after intranasal administration in migraine was evaluated. Twenty patients, with a history of migraine of > 1 year and with two to eight migraine attacks per month, were included in an open trial. A baseline period was followed by an active treatment period of 3 months with 1 mg intranasal hydroxocobalamin daily. Patients were instructed to complete a diary in which details of each attack were described. A reduction in migraine attack frequency of >/ or = 50% was seen in 10 of 19 patients, which corresponds to 53% of the patients (responders). A reduction of > or = 30% was noted in 63% of the patients. The mean attack frequency in the total study population showed a reduction from 4.7 +/- 1.7 attacks per month to 2.7 +/- 1.6 (P < 0.001). For the responders the migraine attack frequency was reduced from 5.2 +/- 1.9 (baseline) to 1.9 +/- 1.3 attacks per month (P < 0.005), while for those who did not respond a non-significant reduction was found: 4.1 +/- 1.4 to 3.7 +/- 1.5 (P > 0.1). A reduction was also observed for the total duration of the migraine attacks per month, the total number of migraine days per month and the number of medication doses for acute treatment used per month. This is the first prospective, open study indicating that intranasal hydroxocobalamin may have a prophylactic effect in migraine. As a percentage of responders in prophylactic trials of > 35-40% is unlikely to be a placebo effect, a double-blind study is warranted.

Adult↗
PubMed1999

Bioavailability of intranasal formulations of dihydroergotamine.

OBJECTIVE: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. METHODS: Two intranasal formulations of DHEM in combination with randomly methylated beta-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray (= two puffs of 100 microliters); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray (= four puffs of 125 microliters); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. RESULTS: No statistically significant differences were found in maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under plasma concentration-time curve (AUC0-8 h), Frel(t = 8 h) and Cmax/AUC(t = 8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. CONCLUSION: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers.

Absorption↗
PubMed1997

Falsification of Thai dianabol.

The use of drugs to enhance performance in sport will continue despite drug testing procedures and information campaigns. No attention is paid to the quality of these illicit drugs, as they are obtained through a circuit not monitored by the official authorities. A falsification of 'Thai Dianabol', an anabolic steroid, is reported. The tablets contained methyltestosterone and clenbuterol instead of methandrostenolone. Two patients were admitted to the hospital with symptoms due to clenbuterol poisoning.

Anabolic Agents↗
PubMed1995

Absorption of clonazepam after intranasal and buccal administration.

Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross-over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/- 1.0 ng ml-1 (mean; +/- s.d.) was measured 17.5 min (median) (range 15-20 min) after intranasal administration. A second peak (4.6 +/- 1.3 ng ml-1) caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After buccal administration a Cmax of 6.0 +/- 3.0 ng ml-1 was measured after 50 min (range 30-90 min) with a second peak of 6.5 +/- 2.5 ng ml-1 after 3.0 h (range 2.0-4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/- 18 ng ml-1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection.

Absorption↗
PubMed1994

Urinary concentrations of fosfomycin after a single 3 g dose of fosfomycin to elderly nursing-home patients.

The urinary concentrations of fosfomycin in 7 elderly patients with impaired renal function (mean creatinine clearance 40 ml/min) were studied after a single oral dose of 3 g fosfomycin as the trometamol salt. Urine samples were collected as 12 h portions for 84 h. Urinary concentrations of fosfomycin were 1,383 mg/l (range 314 to 4,200 mg/l) in the first 12 h and gradually declined to 165 mg/l (range 65 to 365 mg/l) between 36 and 48 h. 37% of the oral dose was recovered in the urine unchanged after 84 h, but a wide range (15-60%) in urinary recovery was observed. The elimination half-lives in the patients (estimated from the renal excretion profile of fosfomycin) ranged between 7 and 24 h. These data suggest that the urinary levels obtained in this patient population exceed the minimum inhibiting concentration of the usual pathogens involved in uncomplicated cystitis for at least 48 h. After 24 h the urinary concentrations of fosfomycin are higher than those reported for healthy young subjects.

Administration, Oral↗
PubMed1992

Is Recormon less painful than Eprex after subcutaneous administration?

In this study, we examined the differences in pain score after subcutaneous injection of the epoetin preparations Eprex and Recormon. Patients (n = 30) received 5 injections Eprex and 5 injections Recormon in a randomized double-blind sequence. 10 Min after receiving the injection the patient was asked to complete a visual and a verbal analogue scale and two descriptive scales. The results of 25 patients were used for statistical evaluation. The overall results indicate that there are significantly more patients reporting pain after subcutaneous injection of Eprex than after Recormon (11 versus 2 patients, p less than 0.05; McNemar test). 12 Patients reported no differences in pain. 43 Out of 123 injections Eprex and 69 out of 125 injections Recormon caused no pain (p less than 0.01; chi 2 9.455). For 4 patients Recormon was significantly (p less than 0.05) less painful than Eprex. It can be concluded that Recormon may be a less painful alternative for individual patients reporting pain after subcutaneous injection of Eprex.

Adult↗
PubMed1992

Pharmacokinetics of amoxycillin in elderly in-patients.

The pharmacokinetics of amoxycillin (500 mg) given by intravenous injection and as two oral formulations on three consecutive days were investigated in eight frail elderly in-patients. Marked interindividual variation was found in all kinetic parameters after intravenous injection. The area under the curve (AUC) ranged from 32 to 155 mg.l-1.h and the distribution volume ranged from 13 to 37.1. The mean plasma clearance was 109 ml/min (range 53 to 255 ml/min). Elimination half-life ranged from 1.6 to 3.0 h (mean 2.4 h). The absolute bioavailability after oral administration was highly variable and ranged from 24 to 86% (mean 55%). The bioavailability of the two formulations was not significantly different. The performance of a pharmacokinetic study in these patients was very difficult, regarding their inability to tolerate an intravenous infusion, incontinence, disruption of everyday routine and problems with drinking the required volume of water.

Aged↗
PubMed1992

Intranasal administration of estradiol in combination with progesterone to oophorectomized women: a pilot study.

A pilot study was done to investigate the pharmacokinetics and acceptability of an intranasal 17 beta-estradiol/progesterone formulation. This formulation contained dimethyl-beta-cyclodextrin as a solubilizer and absorption enhancer of the steroid hormones. The study was performed in four oophorectomized and hysterectomized patients. After nasal delivery of 0.34 mg estradiol and 0.85 mg progesterone, concentration-time curves of progesterone, estradiol and its metabolite estrone were established. Rapid absorption of progesterone and estradiol was demonstrated. Progesterone peak-levels (3.9-6.7 nmol/l) exceeded the levels which are found in the follicular phase of the menstrual cycle, but did not reach the levels of the luteal phase. Comparison with an earlier reported study in which only estradiol was administered shows that the addition of progesterone does not alter the absorption and pharmacokinetics of estradiol. The nasal formulation was well accepted by the four patients and no adverse effects were noted.

Administration, Intranasal↗
PubMed1991

Ofloxacin intravenous. Compatibility with other antibacterial agents.

The physical and chemical compatibility of ofloxacin (infusion solution 100 ml = 200 mg) with amoxicillin, amoxicillin + clavulanic acid, flucloxacillin, tobramycin, gentamicin, clindamycin, vancomycin, ceftazidime and piperacillin was investigated. Upon admixture with flucloxacillin a precipitate formed between 7 and 24 hours. No other physical or chemical incompatibilities were observed with any of the other combinations. Ofloxacin may be safely combined with the tested antimicrobial drugs, except for flucloxacillin.

Anti-Bacterial Agents↗
PubMed1991

Intranasal estradiol administration to oophorectomized women.

An open, dose-finding study into the effects of a new intranasal 17 beta-estradiol formulation using dimethyl-beta-cyclodextrin as a solubilizer was conducted in nine hysterectomized and oophorectomized patients with symptoms of estrogen deficiency. After nasal delivery of 0.34 mg estradiol in three patients, concentration-time curves of estradiol in serum and its metabolite estrone in plasma were established. High initial estradiol serum levels were found in the order of 5 nmol/l. Estrone/estradiol ratios were below unity, whereas, in contrast, estrone/estradiol ratios after oral administration of estradiol are known to exceed unity. Biological activity, as reflected by suppression of FSH and LH, was manifest. In nine patients symptoms of estrogen deficiency were assessed by a questionnaire. After 3 and 6 months of treatment, a clinically and statistically significant decrease (P less than 0.01) of the total score according to this questionnaire was found compared to the beginning of the study. Thus nasal delivery of estradiol using this cyclodextrin formulation has potential for further clinical evaluation.

Administration, Intranasal↗
PubMed1991

Comparison of steady-state serum concentrations of digoxin in tablets (Lanoxin) and capsules (Lanoxicaps) in the elderly.

The bioavailability of digoxin in solution (Lanoxicaps, 90-100 percent) is superior to that of Lanoxin tablets (60-80 percent) in young healthy volunteers. The alleged bioequivalence of digoxin in tablets (Lanoxin 0.25, 0.125 mg) and capsules (Lanoxicaps 0.2, 0.1 mg) was studied in 20 elderly inpatients (14 women, 6 men, aged 84 +/- 5 years), treated with digoxin for atrial fibrillation. In a crossover design, steady-state digoxin concentrations were measured in 16 patients after once-daily administration of Lanoxin 0.125 mg or Lanoxicaps 0.1 mg, each for at least ten days. Four other patients took Lanoxin 0.25 mg and Lanoxicaps 0.2 mg successively. The steady-state digoxin concentrations were statistically significantly different, being 1.3 +/- 0.5 nmol/L for Lanoxin and 0.9 +/- 0.4 nmol/L for Lanoxicaps (p = 0.003). Whereas in young healthy volunteers the bioavailability of digoxin from Lanoxicaps (90-100 percent) exceeds that from Lanoxin (80 percent), in elderly patients the absorption appears to be similar. This suggests a lower than expected bioavailability of Lanoxicaps, which may result in subtherapeutic serum concentrations.

Aged↗