Biomedical subjects
Publications and source records attributed to S J Mather.
The central hypoventilation syndrome (Ondine's curse) is reviewed and discussed with emphasis on the clinical features and treatment of the disorder. It is a rare syndrome, but the anaesthetist working in a paediatric centre or in intensive care should be aware of its existence since advice and assistance in management may be required.
A technique for labeling monoclonal antibodies (MoAb) with large activities of radioiodine using the reagent N-bromosuccinimide is described. This technique has been used to label three tumor-associated antibodies with an average labeling efficiency of greater than 90%. No significant damage to the antibody could be detected by enzyme linked immunosorbent assay (ELISA), performed immediately after the labeling procedure. Because high radiochemical purity can be achieved without the need postlabeling purification, the procedure is rapid and results in very low radiation doses to staff.
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Plasma concentrations of etomidate have been measured in six patients who required intermittent positive pressure ventilation following surgery. There was an approximately linear relationship between the plasma concentration and the rate of infusion of etomidate. The drug exhibited linear pharmacokinetics over a 10-fold variation in plasma concentration. The decrease in the plasma concentration after discontinuing the infusion was consistent with a three-compartment pharmacokinetic model. The plasma terminal half-life was found to be about 5.5 h, and the clearance calculated to be 0.025 litre kg-1 min-1.
A resumé of two studies and retrospective survey of 52 patients in an intensive care unit receiving infusions of etomidate has demonstrated that the technique can be used effectively and safely to provide sedation in patients requiring artificial ventilation and those breathing spontaneously. In both studies all measured respiratory and cardiovascular indices remained within normal limits. There was a low incidence of muscle movements in all groups and there was no nausea, vomiting, or allergic reactions. Additionally, the technique was readily accepted by the patients.
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The management of a case of status asthmaticus complicated by surgical emphysema is described. In view of voice changes, intubation was necessary but intermittent positive pressure ventilation was considered unwise, because of the surgical emphysema. A means of maintaining adequate sedation in an intubated patient whilst allowing spontaneous respiration is outlined.
A technique is described for sedation of ventilated patients. Six patients who underwent major maxillofacial surgery were given low dose infusions of etomidate and fentanyl for postoperative sedation. Measurements of respiratory function were recorded before and during the period of intermittent positive pressure ventilation. Plasma etomidate levels were estimated. After initial stabilisation on almost constant rate of infusion was used to provide a reproducible level of sedation from which the patients were easily aroused. All patients maintained an adequate minute volume when disconnected from the ventilator. All measured and derived respiratory indices remained within normal limits. Patients exhibited amnesia throughout the period of infusion. All patients found this method of sedation pleasant. This technique may be recommended as an alternative to conventional methods of sedation for ventilated patients.
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Gold salts and phenylbutazone selectively inhibit the synthesis of PGF2alpha and PGE2 respectively. Lowered production of one prostaglandin species is accompanied by an increased production of the other. Selective inhibition by these drugs was observed in the presence of adrenaline, reduced glutathione and copper sulphate under conditions when most anti-inflammatory compounds inhibited PGE2 and PGF2alpha syntheses equally. It is postulated that selective inhibitors may have a different mode of action in vivo and beneficial effects may be related to the endogenous ratio of PGE to PGF required for normal function.
Octreotide is a synthetic analog of the peptide hormone somatostatin (SMS). A wide variety of tumors express enhanced numbers of SMS receptors, notably neuroendocrine tumors and lymphomas, but also some of the more common adenocarcinomas. Octreotide contains only eight amino acids, some of which are in the (D) configuration in order to enhance the stability of the molecule in vivo. Tyrosine and DTPA-containing analogs of octreotide have been synthesized and labeled with iodine-123 and indium-111, respectively, with the intention of targeting SMS receptor-containing tumors for diagnostic purposes. Both radiopharmaceuticals demonstrate a high sensitivity and specificity for these tumors, indicating a clinical role for these agents in management of these diseases. Lessons can be learned from the success of these agents when designing improved antibody-based molecules. Tumor uptake of radiolabeled octreotide is very rapid, occurring within minutes of administration. Blood clearance is also rapid, such that tumors are soon visible even in areas of high blood background. An interesting finding has been the differences between the pharmacokinetics of the iodinated and indium-labeled species. Although the majority of 123I-Tyr3-octreotide undergoes hepatobiliary excretion, 111In-DTPAPhe1-octreotide is eliminated predominantly by the kidneys. These results suggest that the smallest possible antibody-like tracers are likely to have advantages over native immunoglobulins and conventional Fab-like fragments.
Cross-linked F(ab')2 fragments derived from PR1A3, a murine monoclonal antibody used in radioimmunoscintigraphy of colorectal tumors, were produced using the bifunctional reagent bismaleimidohexane (BMH) as follows: Digestion of PR1A3 with pepsin gave F(ab')2 fragments which were purified by ion-exchange chromatography. Fab' was produced by reduction of F(ab')2 with cysteine. Following reaction with BMH, cross-linked F(ab')2 fragments, XL-F(ab')2, were isolated by preparative size-exclusion HPLC. Analysis by HPLC and SDS-PAGE demonstrated the presence of a molecule of approximately 100 kDa containing a nonreducible 50,000 MWt chain. Competitive and direct radioligand binding assays demonstrated that the XL-F(ab')2 had a capacity to bind to antigen similar to that of unmodified F(ab')2. The biodistribution of 125I-labeled XL-F(ab')2 and unmodified F(ab')2 was compared in a nude mouse human tumor xenograft model at 4, 24, and 48 h after injection. Differences between the two preparations were most significant after 24 or 48 h. Tumor uptake of the XL-F(ab')2 was greater and normal tissue retention less than with the unmodified fragment. Tumor to normal tissue ratios at 48 h ranged from 6.2 to 35.2 for XL-F(ab')2 while for the normal F(ab')2 they ranged from 1.5 to 14.2. These results suggest that cross-linked antibody fragments may produce better tumor targeting in clinical application.
We have labeled a series of short peptides with technetium-99m either by direct labeling at pH 11 or by exchange from [99mTc]technetium glucoheptonate. Typical labeling yields obtained were as follows: N-acetyl-Gly-Cys(S-Acm)-Gly-Cys(S-Acm)-Gly-NH2 (Acm = acetamidomethyl) 99%, S-benzoyl-mercaptoacetyltriglycine (S-Benzoyl-MAG3) 95%, mercaptoacetyldiglycine-NH2 (MAG2-NH2) 94%, MAG3 92%, N-acetyl-Aib-Aib-Cys-NH2 (Aib = aminoisobutyric acid) 91%, Gly-Gly-Gly-Gly 90%, N-acetyl-Gly-Gly-Cys-Gly 87%, cyclo-1, 4-(Gly-Gly-Gly-Gln) 40%, S-methyl-MAG2-NH2 0%. In the absence of cysteine, all of the labeled peptides were quite stable in solution, with at least 80-90% of the labeled peptide remaining at 24 h. The order of stability of the labeled peptides to challenge with cysteine was found to be MAG3 > S-benzoyl-MAG3 > N-acetyl-Gly-Cys(S-Acm)-Gly-Cys(S-Acm)-Gly-NH2 >N-acetyl-Aib-Aib-Cys-NH2 > MAG2-NH2 > N-acetyl-Gly-Gly-Cys-Gly > cyclo-1,4-(Gly-Gly-Gly-Gln) > Gly-Gly-Gly-Gly. The peptides without a sulfur donor were least stable to challenge with cysteine.
The synthesis of conjugates of two somatostatin analogues, RC-160 and [Tyr3]octreotide with different bifunctional chelators for labeling with Tc-99m, is described. Conjugates with hydrazinonicotinamide (HYNIC) and two N3S compounds (benzoyl MAG3 and a N3S adipate derivative) were prepared on a small scale with high purity allowing evaluation of different bifunctional chelators on the same peptide without extensive peptide synthesis. High in vitro stability and retained binding affinity was found for all conjugates except for the N3S adipate. Peptide conjugates could be labeled at high specific activities (>1 Ci/micromol) with 99mTc, and different coligands were explored for the HYNIC conjugates. The resulting radiolabeled complexes were highly stable and showed binding affinity to somatostatin receptors in the nanomolar range. Varying labeling yield, stability, lipophilicity, and isomerism were found for different coligands used for labeling HYNIC conjugates, with lower lipophilicity, higher stability, and fewer coordination isomers for EDDA and tricine/nicotinic acid as ternary coligand compared to tricine. In particular, HYNIC complexes showed promising results for further in vivo evaluation.
A new monoclonal antibody, SM3, against stripped mucin core protein has been evaluated for the radioimmunoscintigraphy of ovarian cancer. It was radiolabelled with In-111, I-123 and Tc-99m and results showed a sensitivity of 95%, 100% and 100% and an accuracy of 73%, 86% and 100% for malignancy; respectively.
There is nowadays virtually no contraindication to anaesthesia for even small, sick neonates provided that adequate resuscitation is first carried out. Furthermore, apart from severe trauma and airway difficulties, very few paediatric surgical emergencies require immediate intervention. Most emergencies can be treated within a few hours, preferably when the full facilities of the hospital are available.