Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents

A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.     

Exchange-transfusion with pyridoxalated polymerized hemoglobin: effects on liver PO2

To examine the efficacy of modified stroma-free hemoglobin in maintaining liver PO2, rats were exchange-transfused to hematocrit 10% using pyridoxalated polymerized hemoglobin (plp-polyHb, 10-12 g/dl) prepared from crystalline Hb. Following hemodilution, plasma Hb was 7.4 g/dl, and rats were normotensive. Mean liver PO2 was 3.4 vs 23.3 mm Hg in sham-exchanged controls. Other rats, hemodiluted similarly with 6% albumin or hydroxyethylstarch, were hypotensive and died. At 24 hours plasma Hb was 2.0 g/dl, indicating an intravascular half-life of approximately 16 hours. Hepatic PO2 was 12.4 vs 26.8 mm Hg in nonhemodiluted controls. Data provided by clearance of low-dose indocyanine green suggested reduced plasma volume and depressed liver blood flow. Scattered foci of midzonal hypoxic damage were observed in liver lobules. The basis for hypoxic injury is considered to be due in part to the acute restriction of oxygen supply induced by exchange-transfusion with plp-polyHb. The rate of loss of intravascular hemoglobin and diminished plasma volume could have contributed to oxygen insufficiency as well. Endotoxin present in the plp-polyHb was not a factor.     

Early and late dilatation for acquired subglottic stenosis

There has been widespread use of periodic dilatations in the management of subglottic stenosis. However, some authorities have questioned the value in the overall rehabilitation of patients affected by this disorder. The first phase of this study included fourteen large dogs in which acute subglottic lesions were created by use of a high-speed electric drill and electrocautery. Twelve animals served as the experimental group and two animals were controls. Obstructing lesions developed in all the animals within 7 to 21 days. When at least a 50% obstruction developed in an animal, a treatment plan was instituted that included at least weekly dilatation, removal of granulations, and administration of intralesional steroids and/or systemic steroids and antibiotics. The two control animals became totally obstructed and were killed. Varying degrees of subglottic stenosis developed in all twelve experimental animals after 8 weeks of dilatation, but none required a tracheotomy. These twelve animals were then subjected to 8 additional weeks of dilatation and antibiotics, and supplemental steroids were used in some animals from this study. It can be concluded that early periodic dilatation and granulation removal in the acutely injured subglottis is effective in prevention of severe stenosis, late periodic dilatations in chronic subglottic stenosis are not helpful in further alleviation of obstruction, the concomitant use of antibiotics and systemic steroids did not appreciably prevent or alter the development of subglottic stenosis, and the concomitant use of intralesional steroids appeared to be of benefit in the management of chronic acquired subglottic stenosis.     

Case-control study of prenatal ultrasonography exposure in children with delayed speech.

OBJECTIVE: To determine whether there is an association between prenatal ultrasound exposure and delayed speech in children. DESIGN: Case-control study. SETTING: Network of community physicians affiliated with the Primary Care Research Unit, University of Calgary. SUBJECTS: Thirty-four practitioners identified 72 children aged 24 to 100 months who had undergone a formal speech-language evaluation and were found to have delayed speech of unknown cause by a speech-language pathologist. For each case subject the practitioners found two control subjects matched for sex, date of birth, sibling birth order and associated health problems. MAIN OUTCOME MEASURES: Rates of prenatal ultrasound exposure and delayed speech. RESULTS: The children with delayed speech had a higher rate of ultrasound exposure than the control subjects. The findings suggest that a child with delayed speech is about twice as likely as a child without delayed speech to have been exposed to prenatal ultrasound waves (odds ratio 2.8, 95% confidence limit 1.5 to 5.3; p = 0.001). CONCLUSION: An association between prenatal ultrasonography exposure and delayed speech was found. If there is no obvious clinical indication for diagnostic in-utero ultrasonography, physicians might be wise to caution their patients about the vulnerability of the fetus to noxious agents.     

An Alternative Surgical Technique in Orthotopic Cardiac Transplantation

A bstract Forty patients underwent orthotopic cardiac transplantation at Wythenshawe Hospital between May 1991 and November 1992. Twenty patients had transplantation using an alternative technique that preserves the shape of the left atrium and leaves the right atrium intact (group A). The remaining twenty had conventional transplantation using the technique described by Lower and Shumway (group B). The patients were randomized to either the new or the conventional technique on an alternate basis. There was no mortality in group A, but two patients in group B developed right ventricular failure and died. Two patients in each group developed nodal rhythm and all four recovered sinus rhythm. Echocardiography and Doppler velocimetry at the transvalvular level confirmed normal atrial function in group A with erratic atrial contraction wave in group B. There was also slightly lower incidence of mitral and tricuspid valve regurgitation in group A than in group B. The improved atrial function in group A may play a part in the prevention of right sided failure following cardiac transplantation.     

Effect of endothelium on beta-VLDL metabolism by cultured smooth muscle cells of differing phenotype

The effect of endothelial cells (EC) on the binding and internalisation of beta-very low density lipoprotein (beta-VLDL) and the subsequent accumulation of lipid was investigated in cultured smooth muscle cells (SMC) of different phenotype. The following combinations were examined: (i) SMC cultured and incubated with 125I-beta-VLDL without EC: "control" cultures; (ii) SMC co-cultured with EC and incubated with 125I-beta-VLDL without EC: "separated" cultures; and (iii) SMC co-cultured with EC and incubated with 125I-beta-VLDL in the presence of EC: "co-incubated" cultures. SMC were in the contractile (CON), reversible synthetic (RS) or irreversible synthetic (IRS) phenotype and EC were either actively proliferating or confluent and quiescent. All three SMC phenotypes showed the greatest capacity to bind and internalise 125I-beta-VLDL with accumulation of lipid when "co-incubated" with confluent EC. SMC "co-incubated" with proliferating EC showed a lower capacity to bind and internalise the lipoprotein and accumulate lipid, while "control" SMC showed the lowest capacity for all phenotypes. IRS SMC bound more 125I-beta-VLDL than either RS or CON state phenotypes. In addition, IRS SMC "co-incubated" with confluent EC showed the greatest degree of binding, and IRS SMC incubated with EC-conditioned medium and EC-conditioned 125I-beta-VLDL showed a significant increase in binding above control (fresh medium and fresh 125I-beta-VLDL). The degree of binding 125I-beta-VLDL to SMC was affected by the functional state of the EC. That is, SMC "co-incubated" with confluent EC bound more lipoprotein than SMC "co-incubated" with the same number of proliferating EC. These results are consistent with observations by others who report preferential lipid accumulation in regions of denuded artery recently recovered by endothelium compared with regions lacking an endothelium. The results also indicate that the EC both modify the beta-VLDL particle and affect the biology of the SMC themselves.     

Role of computed tomography in screening for hepatocellular carcinoma in patients with cirrhosis

One hundred patients with cirrhosis underwent abdominal computed tomography (CT) using a delayed contrast technique to determine liver and spleen volume. These scans were reviewed to screen this "at risk" population for hepatocellular carcinoma (HCC). Fifteen of the 100 screened patients had focal abnormalities suspicious for HCC. On biopsy, only 1 patient was shown to have HCC. The other 14 patients had either fatty infiltration or focal regeneration. In the same time interval, a total of 10 patients had histologically proven HCC. All presented with symptoms and died within 4 months of diagnosis. The results show that focal hepatic lesions can be detected by CT but in this population the lesions may not be due to HCC. The incidence of HCC was approximately 1%, probably reflecting a truly low incidence in this population.     

Petit Mal-Grand Mal ECT: A Method to Induce Seizures Without Barbiturate Anesthesia

Petit mal-grand mal (PM-GM) electroconvulsive therapy (ECT) is a technique developed by Impastato to elicit unconsciousness with a subconvulsive electrical stimulus, rather than with barbiturate anesthesia. Muscle relaxation is produced with succinylcholine chloride before stimulus is applied. The cases reported here illustrate applications of the technique to depressed patients with severe cardiac and pulmonary disease, and the use of PM-GM ECT in a patient in whom seizures could not be elicited by the usual ECT technique is described.     

Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor

Developing rats are far more sensitive than adults to the behavioral effects of haloperidol. The present results support the hypothesis that this change may reflect age-related changes in brain responses such as alterations in drug-receptor or drug-effector mechanisms. Dose-response studies of catalepsy and ptosis were conducted in male Sprague-Dawley rats aged 30, 56, or 100 days. Resulting dose-effect curves were approximately parallel and showed rightward shifts with highly significant progressive increases of ED₅₀. Similar developmental decreases in drug sensitivity (3–6 ×) were found following systemic (PO or IP) administration of haloperidol or the phenothiazine neuroleptic perphenazine, which differ markedly in structure, potency, distribution, and metabolism. Age-related decreases in drug sensitivity (3–4 ×) were also found using intracerebroventricular (ICV) administration of both agents in an attempt to bypass potential pharmacokinetic influences. Since the age-dependent decrease in sensitivity to both neuroleptics was found during the rising phase of drug action (1st hour) and ranked: PO>IP>ICV, some change in absorption and distribution of both drugs may occur in addition to the apparently important maturational decrease in target-organ sensitivity indicated by the responses to direct ICV injection and by the similarity of results obtained with dissimilar agents.     

Laboratory and clinical evaluation of the impact Uni-Vent 750 portable ventilator

BACKGROUND: Transportation of critically ill, mechanically ventilated patients from intensive care units for diagnostic and therapeutic procedures has become common in the last decade. Maintenance of adequate oxygenation and ventilation during transport is essential. We evaluated the Impact Uni-Vent 750 portable ventilator in the laboratory and in the clinical arena to determine its usefulness during inhospital transport. MATERIALS & METHODS: In the laboratory, we determined the Uni-Vent 750's ability to assure tidal volume (VT) delivery in the face of decreasing compliance of a test lung and tested the alarm systems. Using a two-compartment lung model modified to simulate spontaneous breathing, we also evaluated the responsiveness of the demand valve. The clinical evaluation was accomplished by comparing arterial blood gas values and ventilator settings in the intensive care unit before transport to those during transport. RESULTS: As lung compliance was reduced from 0.1 to 0.02 mL/cm H2O [1.0 to 0.20 L/kPa], a slight, statistically insignificant decrease in delivered tidal volume was observed. All alarm systems operated according to manufacturer's specifications. The demand valve triggered appropriately with PEEP from 0 to 20 cm H2O [0 to 1.96 kPa]. Sensitivity settings less than -6 cm H2O [-0.59 kPa] sometimes resulted in inability to trigger the demand valve. During patient transport, arterial blood gas values and ventilator settings were comparable to those observed in the ICU. Because an FIO2 of 1.0 was used during transport, mean (SD) PaO2 was significantly greater 89 (26) vs 341 (78) [11.8 (3.5) vs 45.3 (10.4) kPa]. CONCLUSIONS: The Uni-Vent 750 is a reliable transport ventilator, capable of maintaining adequate oxygenation and ventilation in a majority of mechanically ventilated patients. The Uni-Vent 750's ability to (1) provide CMV, AMV, and SIMV; (2) provide low and high pressure alarms; and (3) provide PEEP compensation is unique among portable ventilators.