Infusion labelling

A further complexity in the distribution of thyroid hormones to the CNS is seen in studies of the equilibration of continuously infused labeled hormones with tissues. The ratio of T3 derived from injected to T3 derived from plasma fails to achieve equilibrium with the plasma and other organs, and the brain maintains a ratio higher than in other tissues. Studies of this kind that focus on specific regions of the brain would be of interest. It is also important to note, especially in the context of this symposium, that hormone accumulation in the brain varies during maturation. Brain uptake of in 10 day old rats is 3 times higher than in 30 day old rats. ... 

In a prospective, open-label study, Hill et al. assessed the feasibility of a bridging approach using full-dose IV rt-PA. Following IV infusion of 0.9 mg/kg rt-PA, six patients underwent lAT with rt-PA (maximum dose 20 mg) and one underwent intracranial angioplasty. TIMI 2 or 3 recanalization was achieved in three of these patients. There were no symptomatic ICHs. 

The Interventional Management of Stroke (IMS I) Study was a multicenter, open-labeled, single-arm pilot study in which 80 patients (median NIHSS 18) were enrolled to receive IV rt-PA (0.6 mg/kg, 60 mg maximum, 15% of the dose as a bolus with the remainder administered over 30 minutes) within 3 hours of stroke onset (median time to initiation 140 minutes). " Additional rt-PA was subsequently administered via a microcatheter at the site of the thrombus in 62 of the 80 patients, up to a total dose of 22 mg over 2 hours of infusion or until complete recanalization. Primary comparisons were with similar subsets of the placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. The 3-month mortality in IMS I subjects (16%) was numerically lower but not statistically different than the mortality of the placebo (24%) or rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic ICH (6.3%) in IMS I subjects was similar to that of the rt-PA-treated subjects (6.6%) but higher than the rate in the... 

FIGURE 31 -10 Cerebral amino acids and carbohydrates incorporate 13C label from infused glucose. The top panel shows a 13C NMR spectrum obtained from a gray-matter-rich volume in the human head. (From reference [141].) The right panel shows label incorporation into brain glycogen and glucose in humans. (From reference [142].) The stack plot illustrates the rate of label incorporation into many compounds and carbons in the rat brain. (From reference [ 143].) In all studies, glucose labeled at the 1 or 6 position was administered intravenously. 

Quantitative aspects of the pattern of nicotine metabolism have been elucidated fairly well in people (Fig. 4). Approximately 90% of a systemic dose of nicotine can be accounted for as nicotine and metabolites in urine (Benowitz et al. 1994). Based on studies with simultaneous infusion of labeled nicotine and cotinine, it has been determined that 70-80% of nicotine is converted to cotinine (Benowitz and Jacob 1994). About 4-7% of nicotine is excreted as nicotine N -oxide and 3-5% as nicotine glucuronide (Benowitz et al. 1994 Byrd et al. 1992). Cotinine is excreted unchanged in urine to a small degree (10-15% of the nicotine and metabolites in urine). The remainder is converted to metabolites, primarily fra i -3 -hydroxycotinine (33 0%), cotinine glucuronide (12-17%), and trans-3 -hydroxycotinine glucuronide (7-9%). 

Labeling of iodinated aromatics with radioactive or has proved to be a valuable approach to measure GFR in nuclear medicine. Prominent among these is sodium iothalamate, which is specifically marketed in the US for GFR measurement by the name Glofil . Studies have shown that the clearance of this marker by the glomeruli is reproducible, simple, reliable and accurate, especially in children and those with advanced renal diseases [234]. This marker can also be administered by subcutaneous infusion to obtain GFR values without the need for urine collection [235]. Since very low doses (nanomolar scale) of radioactive aromatics are administered, monitoring of renal function may be achieved without disruption of normal physiologic functions. Concerns over radioactivity and associated handling costs may prevent the use of these compounds for routine GFR measurements. 

Levels of label in the liver, kidney, and plasma were determined for the donor and recipient rats when secretions from bile duct cannulated donor rats, given a dose of 100 mg/kg hexachlorobutadiene were infused directly into the bile duct of nonexposed recipient rats, and thereby into their intestines (Payan et al. 1991). In the donor rats, after 30 hours, the kidney contained 0.26% of the dose, the liver 0.11%, and the plasma 0.013% from the intestinally absorbed material. In the recipient rats, the kidney contained 0.15% of the dose, the liver 0.97%, and the plasma 0.009% from the resorbed biliary metabolites. For each tissue the level of label from resorbed metabolites was about two-thirds of that from the original dose. The kidneys contained more of the label than the liver in both instances, clearly identifying the kidneys as a target organ. 

The biosynthesis of aristolochic acids is considered to begin with 1-ben-zyltetrahydroisoquinoline precursors and to proceed via aporphine intermediates (5). In radioactive labeling studies, Spenser and Tiwari infused d/-tyrosine-2- C into the stem of A. sipho. The C-labeled aristolochic acid I formed lost more than 60% of its radioactivity when it was decarboxylated to the corresponding nitro phenanthrene derivative. Administration of d/-dihydroxyphenylalanine-2- C re-... 

Similar labeling language also in the labeling of PROGRAF (Fujisawa) tacrolimus capsules, tacrolimus injection (for intravenous infusion only), July 2001 RAPAMUNE (Wyeth-Ayerst) (sirolimus) oral solution and tablets, August 2004 and GENGRAF capsules (Abbott) (cyclosporine) capsules, USP, January 2003. 

In December 2005, Osiris began a phase II clinical study to assess the ability of OTI-010 to reduce inflammation and repair damaged tissue in patients with moderate to severe CD unresponsive to steroids and other immunosuppressants [639559]. In the phase II, randomized, open-label clinical study, OTI-010 will be infused into an expected 12 patients on two separate days, seven to 10 days apart [www.clinicaltrials.gov]. 

Liquid extracts such as infusions will often, over time, produce a fine sediment. There may be a statement to this effect in the specification and on the container label. If the product for which the extract is destined is a cloudy drink or opaque like a fruit juice, then the container can be shaken each time to re-disperse the sediment before weighing out. If it is essential for the extract to be clear, then it must be carefully decanted when weighing out for a production batch. Extracts in storage will often change colour over time. Thus, specifying a colour parameter without a time factor can lead to the situation where a customer s QC accepts the extract on delivery, as it meets colour standards at the time, but rejects it on retesting later after it has spent some time in the raw materials store -particularly if the drum has been opened and is part used. 

Figure 20.1 Distribution volume of Evans blue-labeled albumin in a rat fibrosarcoma as a function of (A) perfusion pressure or (B) perfusion rate. The ratio of distribution volume (Fd)/infused volume ( ] ) was quantified at the infusion pressures of 36, 50, 94, and 163 in cmH20, respectively. Symbols represent data from individual experiments N= 2 for pressure of 36 cmH20 and N=5 for other pressures. The line in (B) was obtained through linear curve-fitting of the data. Reproduced with permission (McGuire and Yuan, 2001).

Figure 20.2 The apparent hydraulic conductivity (Kapp) in fibrosarcomas at different perfusion pressures. The curve labeled with 1-D was obtained during one-dimensional perfusion of tumor slices. The curve labeled with 3-D was obtained during direct infusion into a tumor chunk via a 23G needle. The perfusion pressure varied between 20 cmH20 and 163 cmH20. The threshold pressures in 1-D and 3-D experiments are indicated by arrow-head and arrow, respectively. The symbols and error bars represent mean and SD, respectively. The number of tumors for each data point was six in 1-D experiments and three or four in 3-D experiments. Reprinted with permission (Zhang et al., 2000).

Parenteral 40, 80, 160 mg/mL for IV injection 80, 160, 320 mg/dL in 5% dextrose for IV infusion Angiotensin-Converting Enzyme Inhibitors Labeled for Use in Congestive Heart Failure Captopril (generic, Capoten)... 

We performed transient global cerebral ischemia on adult macaque monkeys by reversibly stopping blood flow to the brain. We labeled de novo-generated cells in postischemic animals as well as in sham-operated controls by infusing the DNA synthesis indicator BrdU, and subsequently investigated the distribution and phenotype of BrdU-labeled cells in several telencephalic regions at various time-points after ischemia. 

A single intravenous infusion of 1000 mg iron dextran has also been evaluated in two open label studies, in which idiopathic RLS patients (n = 11) in the one study, and RLS patients with chronic kidney failure (n = 25) in the other study, were included [88, 89], In both investigations, a therapeutic effectiveness was reported for a period of 2 1 weeks, and in one study the authors also noticed a reduction in PLM [88], The results from oral iron therapy seem to be less convincing. In the only double-blind study available in literature, 24 RLS patients were treated for 2 weeks with a daily amount of 325 mg of iron sulfate. Despite the fact that a considerable number of the subjects did not complete the study due to the appearance of side effects, no significant difference in symptom relief was reported between treated and control group. Reduced effectiveness of oral iron therapy could depend... 

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