The influence of anesthetic choice, PaCO2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts.

UNLABELLED: Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors. Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O2 protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [3H]-methotrexate. With isoflurane/O2 anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [3H]-methotrexate delivery compared with saline in the tumor (0.388 +/- 0.03 vs 0.135 +/-0.04; P = 0.0001), brain around the tumor (0.269 +/- 0.03 vs 0.035 +/- 0.03; P = 0.0001), brain distant to the tumor (0.445 +/- 0.05 vs 0.034 +/- 0.07; P = 0.001), and opposite hemisphere (0.024 +/- 0.00 vs 0.016 +/- 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O2 anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/ N2O regimen was compared with the isoflurane/O2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2O was superior to isoflurane/O2 by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N2O regimen was evaluated, and none was found. These data support the use of propofol/N2O along with maintaining hypocarbia to optimize BBBD in animals with tumors. IMPLICATIONS: Propofol/N2O anesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.

Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers.

OBJECTIVE: To compare transient blood-brain barrier disruption (BBBD) by hypertonic mannitol with pharmacological modification of the blood-tumor barrier by the vasoactive peptide bradykinin for delivery of small and large agents to nude rat intracerebral xenografts. METHODS: Female nude rats (n = 104) with 6-day intracerebral human small cell lung carcinoma tumors were treated using BBBD (n = 24), intracarotid bradykinin (n = 38), or saline (controls, n = 32) administered intra-arterially. During or immediately after infusion, the rats were given radiolabeled agent (methotrexate or dextran 70; Dupont NEN, Boston, MA). The rats were killed 10 minutes later, and samples of tumor and brain regions were obtained for scintillation counting. Twenty-two additional rats were examined using magnetic resonance imaging after administering one of two contrast agents (gadoteridol or iron oxide nanoparticles) or saline (controls) in conjunction with BBBD or bradykinin. RESULTS: After BBBD, the delivery of both small (methotrexate) and large (dextran 70) radiolabeled tracers was increased 2- to 6-fold in the tumor and 3- to 20-fold in surrounding brain, as compared with saline controls. After bradykinin treatment, there was minimal change in delivery of methotrexate or dextran 70 to tumor and brain around tumor, with the greatest increase less than 60% over controls. Magnetic resonance imaging demonstrated increased delivery of both small and large contrast agents to the treated hemisphere after BBBD. In comparison, no increased tumor enhancement could be detected after bradykinin treatment. CONCLUSION: BBBD resulted in global delivery of a variety of agents in a wide range of sizes. In this human brain tumor xenograft model, bradykinin was not effective at increasing delivery to the tumor of any agent tested.

Muscle weakness during tricaine anesthesia.

An isolated preparation of tadpole tail muscle was used to assess the peripheral effects of tricaine (3-aminobenzoic acid ethyl ester) at anesthetic concentrations and under physiological conditions. The drug effect on the electrically-evoked twitch was tested using short-pulse durations that elicited synaptically mediated effects or longer-duration pulses that stimulated the muscle directly. Tricaine reduced both types of response anesthetic and even subanesthetic concentrations. At steady state concentrations that produced surgical anesthesia in vivo, tricaine reduced the directly evoked response by about half. It is concluded that tricaine anesthesia has a pronounced peripheral effect on neuromuscular function and that direct effect(s) on muscle are a major component.

Prorenin secretion from human testis: no evidence for secretion of active renin or angiotensinogen.

To determine if the testis secretes active renin and prorenin, we collected internal spermatic venous blood from 29 young men undergoing varicocelectomy and measured plasma prorenin and active renin together with angiotensinogen and testosterone. Prorenin was higher in internal spermatic venous plasma than in peripheral plasma (+5.3 +/- 1.2 (+/- SE) ng/mL.h [+1.21 ng/(L.s)]; P less than 0.001) as was testosterone [+344 +/- 32 ng/mL [(+1193 nmol/L; P less than 0.001], but there was no significant difference in either active renin (-0.74 +/- 0.45 ng/mL.h [-0.17 ng/(L.s)] or angiotensinogen [+12 +/- 24 ng/mL (+0.01 mumol/L)]. These results demonstrate that the testis secretes prorenin, but not active renin or angiotensinogen, into the general circulation. They support the hypothesis that extrarenal renin systems cannot process prorenin to renin.

Succinylcholine: mechanism of fasciculations and their prevention by d-tubocurarine or diphenylhydantoin.

Administration of d-tubocurarine (dTC) or diphenylhydantoin (DPH) was evaluated as a pretreatment to prevent succinylcholine (Sch) evoked fasciculations. Experiments were designed to determine the nature of the drug-drug interactions, sites of interaction, and site of fasciculation suppression. Sch is known to evoke repetitive discharge generation by motor nerve terminals (MNTs). Transmission of these prejunctional discharges causes fasciculations. A cat soleus neuromuscular preparation in situ, which enables recording of nerve action potentials initiated by MNTs, their transmitted muscle action potentials, and the resultant contractile responses, was used to explore Sch effects before and after iv pretreatment with dTC or DPH. dTC is known to act prejunctionally to suppress repetitive discharges initiated by facilitatory drugs and tetanic conditioning of MNTs. Accordingly, pretreatment with dTC 50 micrograms X kg-1 suppressed the Sch-induced MNT repetitive discharging and correspondingly suppressed generalized fasciculations without affecting twitch. This dTC dose, however, also reduced Sch blocking potency by 33%, slowed its rate, and shortened block duration. These latter effects represent competitive postjunctional antagonism. DPH is also known to suppress MNT repetitive discharging. Correspondingly, Sch-induced repetitive firing and ensuing fasciculations were suppressed by DPH (30 mg X kg-1) without affecting twitch. Unlike dTC, this DPH dose increased Sch blocking potency by 50%, increased the initial rate of block, and did not alter block duration. These DPH effects were dose-dependent and within the anticonvulsant range for cats. Therefore, patients with anticonvulsant levels of DPH may not require pretreatment before Sch.(ABSTRACT TRUNCATED AT 250 WORDS)

Posterior heel pain associated with a calcaneal step and Achilles tendon calcification.

Factors are examined which may be associated with chronic posterior heel pain of nonrheumatologic and nonmetabolic etiology. The charts of patients in whom Haglund's disease retrocalcaneal bursitis, or "pump bumps" was diagnosed during the period from 1963-1978 at The Hospital for Special Surgery, were reviewed. Nineteen patients met the criteria of symptomatic patients. The radiographs in 12 of these patients were available for review. These cases and 104 control cases were evaluated for the presence of calcaneal spurs, Achilles tendon calcifications and a posterior calcaneal step. In addition, Fowler-Philip measurements were obtained from the radiographs and compared with Fowler and Philip's results. Although the Fowler-Philip angles of the two groups were not significantly different (p greater than 0.05), the symptomatic heels had a significantly longer horizontal calcaneal length (p less than 0.05). The incidences of Achilles tendon calcification (p = 0.004) and of a posterior calcaneal step (p less than 0.001) were higher in patients who had chronic posterior heel pain as compared to a control population. An increased horizontal length of the calcaneus and the presence of a posterior calcaneal step appeared to cause chronic posterior heel pain and degenerative lesions of the Achilles tendon. Although a posterosuperior calcaneal prominence is theoretically important, it was not in this series. A posterior calcaneal step may alter the tension within the tendon, resulting in microscopic tendon injury, decreased vascularity and loss of strength, with subsequent calcification or rupture.