Horton's giant cell arteritis

Giant cell arteritis (GCA) is a spontaneous vasculitic syndrome specifically involving the walls of medium and large arteries. While involvement of other arterial beds is occasionally identified, this syndrome is most frequently recognized when symptomatic involvement of the temporal arteries occurs. Vascular lesions are characterized by patchy granulomatous infiltrates composed of T cells, macrophages, histiocytes, and giant cells. A better prognosis depends on early recognition of the clinical symptoms and prompt treatment. Diagnosis was based on the 5 clinical criteria previously used by the American College of Rheumatology (1990): 1) age 50 years or older; 2) new localized headache; 3) temporal artery tenderness or decrease in temporal artery pulse; 4) erythrocyte sedimentation over 50 mm/ hour; 5) abnormal result on artery biopsy. Giant cell arteritis was considered a rare disease under age 50; however, it is now known to be an important and significant cause of morbidity and mortality in elderly people. Therefore early recognition and treatment with corticosteroid are very important. There is no general agreement concerning the initial dosage, 40-65 mg/day are commonly recommended. After a few months the majority of patients can be treated with a low maintenance dosage of prednisolone (5 to 7.5 mg/day). The mean duration of treatment is about 5 years. The literature is reviewed and the clinical implications of this disease are discussed.     

Diagnosis of canine babesiosis by Percoll gradient separation of parasitized erythrocytes

PURPOSE: To report the development of a bilateral ocular ischemic syndrome despite corticosteroid treatment in a patient with giant cell arteritis. METHOD: Case report. RESULTS: Despite receiving high-dose intravenous methylprednisolone and oral prednisone for biopsy-proven giant cell arteritis that presented as a severe anterior ischemic optic neuropathy in the right eye, a patient developed progressive ocular ischemia in that eye as well as an ocular ischemic syndrome in the fellow eye. CONCLUSIONS: Some patients with giant cell arteritis, possibly patients with other underlying systemic vasculopathies, are refractory to what should be adequate treatment with systemic corticosteroids and may develop a bilateral ocular ischemic syndrome.     

Wuchereria bancrofti microfilaraemia in children in relation to parental infection status

OBJECTIVE: To determine prevalence and severity of carboplatin-induced dose-limiting toxicoses in the cat. ANIMALS: 9 healthy, 6- to 7-month-old cats weighing 4.7 (range, 3.0 to 6.5) kg. PROCEDURE: Cats were given a single i.v. bolus of carboplatin at a dosage of 150 (n = 3), 200 (n = 3), or 250 (n = 3) mg/m2 of body surface area. RESULTS: Dose-limiting neutropenia and thrombocytopenia were significant in all cats given carboplatin at 200 or 250 mg/m2. Weight loss, changes in appetite, and evidence of respiratory difficulty, as well as vomiting, diarrhea, or lethargy were not observed at any time during the 28-day period. At a highest dosage (250 mg/m2), the neutrophil nadir (560 +/- 303 neutrophils/microliters) was observed on day 17 and the platelet count nadir (96,500 +/- 11,815 platelets/microliters) was observed on day 14 after carboplatin administration. CONCLUSIONS: Carboplatin appears to be safe and clinically well-tolerated when given i.v. as a single bolus at a dosage of 200 mg/m2 to clinically normal cats. The dose-limiting toxicity of a single i.v. administered bolus is neutropenia. The nadir of a 200 mg/m2 i.v. administered dose occurs on day 17 (1,110 +/- 165 neutrophils/microliters) and neutropenia (< 2,000 neutrophils/microliters) lasts from day 14 through day 25 after carboplatin administration. CLINICAL RELEVANCE: The fatal dose-related pulmonary toxicosis observed in cisplatin-treated cats was inapparent in carboplatin-treated cats. To adequately determine the therapeutic role of carboplatin in tumor-bearing cats, a moderately tolerated dose of carboplatin of 200 mg/m2 given i.v. once every 4 weeks should be considered.     

Pharmacokinetic approach to the clinical use of lidocaine intravenously

The time course of lidocaine plasma concentrations following various modes of administration were predicted by computer. Initiating therapy with a single intravenous bolus dose was unsatisfactory; plasma levels during the first hour were potentially toxic after a 200-mg bolus and subtherapeutic after a 50- to 100-mg bolus. After two bolus doses of 100 mg, separated by 20 to 30 minutes, or a rapid loading infusion over 15 to 60 minutes, therapeutic concentrations were achieved and maintained. Pharmacokinetic principles can be of value in devising rational approaches to lidocaine dosage.     

Effect of age on pharmacokinetics and pharmacodynamics in man

Elderly patients represent an increasing part of our population who consume disproportionately high amounts of drugs. During aging physiological and disease-induced changes occur which might affect PK and/or PD of many drugs. The calcium channel blocker verapamil and the benzodiazepine midazolam were taken as examples to illustrate some problems and open questions in research pertaining to the elderly. Following an acute i.v. dose of racemic verapamil and during steady-state (120 mg bid p.o.) no significant differences of the stereoselective disposition of S- and R-verapamil could be found between younger and older healthy subjects. Concomitant intake of rifampicin (600 mg/die) induced especially the presystemic (prehepatic) metabolism of verapamil so that oral bioavailability approached zero and PD effects almost diminished. Intestinal metabolism and inducibility were well preserved in the elderly. The PK and PD of midazolam were investigated in young and older patients who received an i.v. bolus of 0.05 and 0.03 mg/kg, respectively, for premedication prior to third molar teeth extraction. Again, no significant differences in the PK parameters were found between both groups. However, the sedative effects were much more pronounced in the elderly and this population demonstrated a significantly higher CNS-sensitivity to midazolam. All physicians should be aware that for various reasons drug response can be age-dependent and therefore more PK-PD data are needed for the elderly.     

Clinical thinking and decision making in the practice. A patient with fever of unknown origin

A 75-year-old woman was admitted because of fever of unknown origin (FUO). In the year before the current admission she developed myalgias and was treated for polymyalgia rheumatica with low-dose prednisone. Her complaints persisted and prednisone was discontinued. Five months before the present admission she developed fever (37.7-38.9 degrees C), malaise, fatigue and occipital headache. Laboratory tests showed an elevated erythrocyte sedimentation rate (98 mm in the first hour) and a severe hypochromic, slightly microcytic, anaemia. Although a recent temporal artery biopsy was negative, a second biopsy was taken which showed giant cell arteritis. The patient was treated with high-dose prednisone (60 mg daily) and made a full recovery. It is emphasized that temporal arteritis is a common cause of FUO in the elderly.     

Dexamethasone pharmacokinetics in clinically normal dogs during low- and high-dose dexamethasone suppression testing

Dexamethasone pharmacokinetics was studied in 10 healthy dogs receiving high-dose administration of dexamethasone (dosage, 0.1 mg/kg of body weight, IV), alone or combined with ACTH (dosage, 0.5 U/kg, IV), or low-dose administration of dexamethasone (dosage, 0.01 mg/kg, IV) in an incomplete cross-over design. Serum samples were obtained at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 720, 1,080, 1,440, 1,920, 2,400, and 2,880 minutes after dexamethasone administration; dexamethasone was measured by radioimmunoassay validated for use in dogs. Dexamethasone pharmacokinetics was adequately described by a two-compartment first-order open model. Comparison of pharmacokinetics for the low- and high-dose protocols revealed dose dependence; area under the curve, mean residence time, clearance, and volume of distribution increased significantly when dexamethasone dosage increased. The elimination rate constant was significantly (P < 0.05) less, and the elimination half-life significantly greater for the high-dose protocols; however, the distribution rate constant and distribution half-life were not significantly different when high-dose protocols were compared with the low-dose protocol. Dose-dependent increases in volume of distribution and clearance may be related to saturation of protein-binding sites. Concurrent administration of ACTH did not affect dexamethasone disposition.     

In-office temporal artery biopsy

Biopsy is essential in the diagnosis of temporal arteritis. Temporal artery biopsy done in the office has many advantages. Patients tolerate the procedure well with little anxiety. There is greater convenience for the patient and ease of scheduling for the referring physician. It can be done promptly and is far more cost-effective than performing the procedure in a surgical center or hospital. Finally, and perhaps most importantly, because the in-office procedure is safe, more convenient, less stressful, and less expensive, clinicians are more likely to obtain a temporal artery biopsy when the diagnosis of temporal arteritis is even a remote possibility. Contrariwise, there is evidence to indicate that many cases of temporal arteritis are not diagnosed because of reluctance to schedule a biopsy. The ophthalmologist is in a unique position to provide help in the diagnosis and follow-up care of the patient with suspected temporal arteritis. Ophthalmologists are familiar with the disease, its treatment, and particularly its ocular manifestations. In addition to the baseline ophthalmic examination to help reveal subclinical pathology, ophthalmologists can evaluate the patient as subsequent visual complaints arise. Finally, by offering a convenient biopsy procedure, the diagnosis can be accurately and promptly confirmed.     

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

ZD9331 is a novel, potent thymidylate synthase (TS) inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.     

Species-specific identification of microsporidia in stool and intestinal biopsy specimens by the polymerase chain reaction

Horton temporal arteritis, or gigantocellular arteritis, is a panarteritis involving the mid-size and large arteries, in particular the temporal surface artery. This pathology is normally found in the elderly, particularly females. It can be manifest with some typical symptoms (i.e. cephalea, fever, visual disorders even leading to blindness mandibular claudication, high ESR, moderate anemia), there may be aspecific, atypical signs (i.e. only cephalea and fever, or widespread myalgia and artralgia) or it may arise following a cerebro-vascular accident. Treatment of this form of arteritis is based on the use of high doses of corticosteroids over a long period of time (at least 1-2 years). The present work describes a surgical technique for biopsying the temporal artery. The technique consists of withdrawal of a segment of the artery from the main branch and the frontal branch of the temporal surface artery. Since this form of arteritis often presents segmentary lesions, it is advisable to take a 4-5 cm sample so as to prevent false negatives. This simple surgical procedure can be performed under local anesthesia and is practically complication-free. The authors then discuss the indications for temporal artery biopsy and report 3 clinical cases (case no. 1 is an example of the classical manifestation while cases no. 2 and 3 are atypical, aspecific forms). Since both the classical and atypical forms of gigantocellular arteritis require high doses of corticosteriods over a long period of time, the temporal artery biopsy procedure is highly useful in formulating an accurate diagnosis. The well known side effects to long-term cortisone use make it necessary to use all the available instruments in making the correct diagnosis. Bilateral biopsy can be performed in those cases where the first biopsy proved negative but gigantocellular arteritis is still suspected.     

Immunohistochemical localization of the spermadhesin AWN-1 in the equine male genital tract

Takayasu's arteritis rarely presents with fever of unknown origin. We describe a 14-year-old girl who was admitted with a 2-month history of fever of unknown origin associated with vague pain in her left upper arm. The constitutional symptoms responded to a trial of steroid therapy for suspected collagen-vascular disease, but flared up when the dose was tapered. An asymmetric radial pulse was recognized incidentally during follow-up examination; diagnosis of Takayasu's arteritis was confirmed by Duplex ultrasonography and angiography. Takayasu's arteritis must be considered when evaluating children with fever of unknown origin, especially those with a positive family history. Careful assessment of the peripheral vascular system with better interpretation of limb symptoms should allow early, appropriate treatment to prevent irreversible vascular damage.     

A phase I study of recombinant human soluble interleukin-1 receptor (rhu IL-1R) in patients with relapsed and refractory acute myeloid leukemia

PURPOSE: The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML). METHODS: The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 microg/m2, s.c. dose 250 microg/m2 per day (five patients); dose level 2 i.v. bolus 1000 microg/m2, s.c. dose 500 microg/m2 per day (three patients); dose level 3 i.v. bolus 2000 microg/m2, s.c. dose 1000 microg/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels. RESULTS: rhu IL-IR was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1beta, IL-6 and TNF were undetectable before, during and after rhu IL-IR administration. The terminal half-life after i.v. dosing was at least 7-12 h, and after s.c. dosing 2-4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease. CONCLUSIONS: rhu IL-1R therapy was safe but did not have any apparent antileukemic effect at the doses administered.     

Heparin therapy in the Chinese--lower doses are required

Warfarin requirements are lower in the Chinese, but it is not known if this applies to heparin. We investigated the optimal dose for heparin therapy in Chinese patients, and to assess relationship between i.v. heparin dosage and anticoagulation efficacy. One hundred Chinese patients requiring intravenous heparin therapy were given an initial bolus followed by continuous intravenous infusion. The main outcome measures were: (i) Efficacy of anticoagulation assessed by blood coagulation studies (APTT) compared to heparin dosage, (ii) Determinants of dosage variation-age, gender, body weight, height, indication for heparin therapy and number of medications, other disease, and serum albumin level. It was found that the mean therapeutic infusion dose requirement of heparin was 848.7 +/- 274.7 units/h, 79% required a dose of 1000 units/h or less. Heparin dose correlated negatively with age (r = -0.40; p < 0.001) and positively with weight (r = 0.44 p < 0.001) and height (r = 0.49; p < 0.001). Chinese subjects require lower heparin doses (about 800 units/h) than usually recommended for Caucasians (usual dose 1000-1500 units/h). This can be partly explained by the lower body weight in Chinese patients.     

Use of aminoglycosides in elderly patients. Pharmacokinetic and clinical considerations

Aminoglycosides still represent a mainstay in the treatment of serious infections caused by Gram-negative bacilli in elderly patients. The aging process is accompanied by various physiological changes (e.g. alterations in body composition, impairments in certain organ functions), which may affect drug disposition and, subsequently, drug action. For aminoglycosides that are eliminated by the renal route, kidney function is the key parameter that should be taken into account when dosage regimens are calculated. Because there is a progressive decline in renal function with aging, the glomerular filtration rate should be estimated for each patient. Any change in creatinine clearance (CLCR) should result in a proportional correction of the dosage regimen. Such individualised dosage of aminoglycosides is particularly important because of their narrow therapeutic indices. There are no conclusive data which indicate that age per se affects the elimination of aminoglycoside antibiotics. Overdosage may result from overestimation of renal function if crude serum creatinine (SCr) levels are used as a guide. Nomograms for the relationship between SCr and CLCR have been developed. However, nomograms should be used with caution because substantial interindividual variability in the plasma concentration-clearance relationship is still observed. Therefore, the choice of a maintenance dose based on an assessment of renal function, which change rapidly, should always be considered as preliminary, and verification by serum concentration measurements is necessary. As a result, the use of aminoglycoside serum concentration monitoring during therapy as the most important guide for dosage adjustment is particularly important in the elderly, and is indispensable in conjunction with frequent assessment of renal function. Although a matter of debate, the value of serum concentration monitoring has been demonstrated. With traditional multiple daily dosage, monitoring peak and trough concentrations has been recommended. For once daily dosage, however, no guidelines relating to therapeutic and/or toxic concentrations are available yet. In the meantime, we recommend monitoring at least trough concentrations. Once daily administration of aminoglycosides has emerged as a new mode of treatment. Compared with multiple daily administration, once daily dosage may have a number of advantages, and many clinical trials comparing the efficacy or safety of both modes have shown either superiority or equivalence of the new mode in most indications. At present, however, no data from studies of once daily administration in young compared with elderly adults are available.     

Color duplex ultrasonography in the diagnosis of temporal arteritis

BACKGROUND: The diagnosis of temporal arteritis usually requires a biopsy of the temporal artery. We examined the usefulness of color duplex ultrasonography in patients suspected of having temporal arteritis. METHODS: In this prospective study, all patients seen in the departments of rheumatology and ophthalmology from January 1994 to October 1996 who had clinically suspected active temporal arteritis or polymyalgia rheumatica were examined by duplex ultrasonography. The final diagnoses, made according to standard criteria, were temporal arteritis in 30 patients, 21 with biopsy-confirmed disease; polymyalgia rheumatica in 37; and negative histologic findings and a diagnosis other than temporal arteritis or polymyalgia rheumatica in 15. We also studied 30 control patients matched for age and sex to the patients with arteritis. Two ultrasound studies were performed and read before the biopsies; one ultrasonographer was unaware of the clinical information. RESULTS: In 22 (73 percent) of the 30 patients with temporal arteritis, ultrasonography showed a dark halo around the lumen of the temporal arteries. The halos disappeared after a mean of 16 days (range, 7 to 56) of treatment with corticosteroids. Twenty-four patients (80 percent) had stenoses or occlusions of temporal-artery segments, and 28 patients (93 percent) had stenoses, occlusions, or a halo. No halos were identified in the 82 patients without temporal arteritis; 6 (7 percent) had stenoses or occlusions. For each of the three types of abnormalities identified by ultrasonography, the interrater agreement was > or =95 percent. CONCLUSIONS: There are characteristic signs of temporal arteritis that can be visualized by color duplex ultrasonography. The most specific sign is a dark halo, which may be due to edema of the artery wall. In patients with typical clinical signs and a halo on ultrasonography, it may be possible to make a diagnosis of temporal arteritis and begin treatment without performing a temporal-artery biopsy.     

The Preterm Prediction Study: recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and therapeutic efficacy of liposome-encapsulated paclitaxel (LET) in comparison to conventional paclitaxel. In normal mice, LET was much less toxic than the conventional drug. A dose of 32.5 mg/kg of conventional paclitaxel administered i.v. on three consecutive days produced 100% mortality by day three, while liposomal paclitaxel exhibited no mortality. The control group which received Diluent 12 (Chremophor EL and ethanol; 1:1 v/v), a vehicle used in conventional paclitaxel, 30% mortality was observed at this dosage level. In murine ascitic L1210 leukemia model, liposomal paclitaxel and conventional paclitaxel showed comparable antitumor activity. The pharmacokinetics of conventional paclitaxel and LET was studied in mice at dose levels of 5 mg/kg and 20 mg/kg. After intravenous administration of conventional paclitaxel at a dose of 5 mg/kg, the area under the plasma-concentration-time curve (AUC) was 2-fold lower and, the elimination half-life was 2-times shorter compared to LET. At a dose of 20 mg/kg, the terminal half-lives were comparable, however, conventional paclitaxel displayed non-linear pharmacokinetics with disproportionate increase in AUC. At the two dose levels studied, LET demonstrated linear kinetics. Tissue distribution of paclitaxel after administration of LET showed levels 10-fold higher in spleen and 3.5-fold higher in liver as compared to conventional paclitaxel. The significant decrease in toxicity shown by LET, coupled with an increase in plasma AUC and half-life indicates that LET may be a viable alternative to the therapeutic use of the conventional preparation of paclitaxel.     

Toxicity management in patients receiving low-dose aldesleukin therapy

OBJECTIVE: To review the pathophysiology and subsequent treatment options for low-dose aldesleukin-induced toxicity when administered via intravenous bolus infusion, continuous intravenous infusion, or subcutaneous injection. BACKGROUND: The adverse events associated with high-dose aldesleukin therapy (600,000 IU per kg i.v. every 8 h for a maximum of 14 doses) are well documented in the literature; however, the adverse event profile of lower doses and alternative administration routes are less well described. An understanding of the adverse event profile associated with these alternative regimens can enhance management of toxicity. DATA SOURCES: English-language clinical studies, abstracts, and review articles pertaining to low-dose intravenous, continuous intravenous infusion, or subcutaneous injection of aldesleukin, as well as aldesleukin-induced adverse events. STUDY SELECTION AND DATA EXTRACTION: Relevant studies were selected that assist with understanding the pathophysiology, clinical management, diagnosis, and management of aldesleukin-induced adverse events. CONCLUSIONS: Aldesleukin therapy initiates a cytokine-mediated proinflammatory process resulting in a toxicity profile that is different from traditional nonbiologic chemotherapeutic agents. The frequency and severity of adverse events associated with aldesleukin administration are dependent upon dose, route, and administration schedule. In addition, most adverse reactions are self-limiting. Alleviation of aldesleukin-induced adverse effects can usually be achieved on an outpatient basis with agents such as antiemetics, antipyretics, and topical creams or lotions, as well as nonmedication interventions. Aggressive and proactive management of aldesleukin associated toxicities can help facilitate completion of therapy.     

PK/PD simulations as a tool for rational design of clinical dosage regimens: an example with Fradafiban

In clinical studies, pharmacodynamic effects should be achieved, e.g. maintenance of certain effects with reversibly acting drugs. Available data base for early phase II studies is frequently kinetics in healthy volunteers from phase I studies and pharmacodynamic effects from in vivo or ex vivo data. Using the fibrinogen receptor antagonist Fradafiban as an example, a procedure to achieve rational dosage regimens is described. Applied methods were: curve fitting of plasma concentrations obtained in phase I studies, correlation of fibrinogen receptor occupancy (FRO) to plasma concentrations using a sigmoid Emax model with Hill coefficient for PK/PD correlation, simulation of time course of FRO for various dosage regimens, using estimates for variability from PK and PD data in order to estimate not only mean values but also expected range of FRO. In a phase II study with Fradafiban administered intravenously, therapeutically active plasma levels had to be achieved rapidly and maintained over 24 hours employing a simple infusion regimen in 20 patients and 3 dose groups. For the target dose, a FRO of 80% should be achieved in most patients. Using the tools mentioned above, a rapid initial infusion rate of 10 mg over 30 minutes, followed by a maintenance infusion of 30 mg for the remaining 23.5 hours for the target dose resulted in a median predicted FRO of 82%. For the lower dose, a 5/15 mg infusion over 0.5/23.5 hours, achieving a predicted FRO of 68% was used and the upper dose (15/45 mg) resulted in 87% FRO. Median experimental results were 84% FRO for the target dose and 73% and 88%, respectively, for the lower and upper dose. As these results fit reasonably well to the predictions, it can be concluded that kinetics in the mostly elderly patients is similar to kinetics in healthy young volunteers. Furthermore, FRO in patients is nearly identical to that in spiked human plasma. Taken together, it could be proven that PK/PD methods are a useful tool for design of clinical studies of Fradafiban.     

Klinefelter syndrome

BACKGROUND: To determine the maximum tolerable dose (MTD) and therapeutic activity of MTHF-modulated FU using two different administration schedules of the antimetabolite (bolus vs. two-hour infusion), the present randomized study using a 'pick-the-winner' design was undertaken in patients with advanced colorectal cancer. PATIENTS AND METHODS: Eighty-two patients with previously untreated advanced measurable colorectal cancer were randomly assigned to treatment with MTHF (100 mg/m2 days 1-5 i.v. bolus) plus FU (400 mg/m2 days 1-5) given either as i.v. bolus injection or as a two-hour infusion every four weeks. In the absence of dose-limiting toxicity (DLT, defined as > or = WHO grade 3 hematotoxicity and/or > or = WHO grade 2 nonhematologic side effects) and evidence of progressive disease, the FU dose was escalated by 50 mg/m2/day during each subsequent cycle until the individual maximum tolerable dose (MTD) was reached. RESULTS: Forty patients were randomized to the FU bolus arm and 42 patients to the FU two-hour infusion arm. The median MTD was 475 mg/m2/day (95% CI: 450-500) in the FU bolus arm with stomatitis +/- diarrhea being the most common DLT. Gastrointestinal side effects were also dose-limiting in the two-hour infusion arm; however, the median MTD was 600 mg/m2/day (95% CI: 568-632). Myelosuppression was more pronounced in the FU bolus arm than in the two-hour infusion arm. The overall response rates were 27.5% (95% CI: 15-44%; 1 CR and 10 PR) for patients treated in the bolus arm and 14.5% (95% CI: 5-28%; 1 CR and 5 PR) for those treated in the two-hour infusion arm. Analogous to recorded response, median time to progression (8.5 vs. 6.25) and overall survival time (14.0 vs. 11.0) tended to be superior in the FU bolus arm. CONCLUSIONS: The observed differences in tolerable drug dose and toxicity between the two treatment arms might be explained by the administration schedule-dependent clinical pharmacokinetics of FU and/or the difference in extent of biochemical modulation of the antimetabolite through MTHF. The fact that the two regimens were not equitoxic probably also helps to explain the favourable response activity noted in the MTHF/FU bolus arm. Whether MTHF is as effective as leucovorin for biochemical modulation of FU remains to be determined in a randomized trial, for which we would recommend its combined use with bolus FU ('winner arm') using a starting dose of 400 mg/m2/day x5.     

Meningiomas of the temporal bone

Meningiomas should be considered in the differential diagnosis of otologic tumors arising from the middle ear and mastoid. It is generally recognized that meningiomas may invade the temporal bone via direct extension from the intracranial space (secondary). It is not generally recognized that meningiomas can develop initially in the middle ear cleft (primary). Representative cases of primary and secondary meningiomas of the temporal bone are described and clinical aspects of diagnosis surgical management are discussed. In order to assess the pathogenesis of meningiomas of the temporal bone, histological studies were done on 200 temporal bone specimens. In certain specimens, ectopic arachnoid granulations, from which primary meningiomas may originate, were identified and described, according to location. One specimen was most unusual in that it contained ectopic glial as well as arachnoidal tissue.