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C Sabin

Publications and source records attributed to C Sabin.

At least 55 records · Page 3Linked to original sources
PubMed1994

The progression of HCV-associated liver disease in a cohort of haemophilic patients.

We have studied morbidity and mortality related to hepatitis C virus infection in haemophilic patients treated at our centre. 11/255 HCV seropositive patients have developed hepatic decompensation. 20 years after first exposure to lyophilized clotting factor concentrate the risk of hepatic decompensation is estimated to be 10.8% (95% CI 3.8-17.8%). There is a significantly increased risk associated with HIV infection, and also with increased age. For HIV seropositive patients the rates of decline in CD4 lymphocyte count and the development of p24 antigenaemia are significant risk factors for hepatic decompensation. Cirrhosis was seen in 9/19 HIV seropositive patients at post mortem. There was an association of cirrhosis with increased age but not with CD4 count, p24 antigenaemia, or AIDS. In conclusion, HCV infection is associated with serious liver disease in haemophilic patients, but so far this has been restricted to a minority of those at risk. HIV co-infection accelerates progression to hepatic decompensation, and we speculate that this is probably due to enhanced HCV replication in the presence of immune deficiency.

Adolescent↗
PubMed1994

CD4+ counts before and after switching to monoclonal high-purity factor VIII concentrate in HIV-infected haemophilic patients.

Allogenic proteins that contaminate intermediate purity clotting factor concentrates may activate the immune system of HIV-infected haemophilic patients. In 37 haemophilic patients infected with HIV who had originally been treated with intermediate purity factor VIII concentrate and then changed to monoclonally-purified high purity factor VIII concentrate the rates of CD4+ decline (10(9)/l per year) were 0.06 before and 0.02 after a switch to high purity products (p = 0.01). The median follow-up of patients after the switch to high purity products was 1.7 years (range 0.2 to 3 years). This significant change in the rate of CD4 decline was independent of the starting CD4 count, age and antiretroviral therapy. This result is consistent with those from randomised trials of the introduction of high-purity concentrate. Given the strong association between the CD4+ count and survival, treatment with high purity rather than intermediate purity clotting factor concentrate may confer a survival benefit for HIV-infected haemophilic patients.

AIDS-Related Opportunistic Infections↗
PubMed1993

New AIDS definition.

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Acquired Immunodeficiency Syndrome↗
PubMed1993

The progression of HIV disease in a haemophilic cohort followed for 12 years.

A cohort of haemophilic patients who seroconverted to HIV-1 between October 1979 and July 1985 has been followed to 1 January 1992. The median age at initial seropositivity was 24 years with a range of 2-77 years. By January 1992, 38/111 (34%) had developed AIDS and 39/111 (35%) had died (four of liver failure including one hepatoma). Using Kaplan-Meier plots, the calculated progression to AIDS at 12 years is 45% (95% CI 31, 58): for age > 25 years 63% (95% CI 45, 82), age < 25 years 32% (95% CI 15, 48) P = 0.0001; CMV positive 68% (95% CI 48, 87) CMV -ve 20% (95% CI 8, 32) P = 0.0009. The 12-year progression rate to CD4 + 0.2 or AIDS is 66% (95% CI 55, 76). 21/34 (63%) of patients who are p24 antigen positive have developed AIDS compared to 17/77 (22%) who are p24 antigen negative (= 0.0001). 19/34 (56%) and 20/77 (23%) of those p24 positive and negative respectively have died (P = 0.007). Before antiviral and prophylactic treatment for asymptomatic patients there were nine AIDS cases in 3.84 years experience with CD4+ < 0.05 (1/0.43 years) and since treatment, 10 AIDS cases in 18.22 years (1/1.8 years). Age, CMV status and p24 remain strongly predictive of disease progression. Treatment appears to reduce the incidence of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Immunodeficiency and the risk of death in HIV infection.

OBJECTIVE: To describe the rate of development of immunodeficiency in human immunodeficiency virus (HIV) infection and to relate this to the risk of death. DESIGN: Inception cohort followed up for up to 12 years from HIV seroconversion until January 1, 1992. SETTING: A regional hemophilia center based in a major teaching hospital. PATIENTS: All 111 patients with hemophilia who seroconverted to HIV-1 between 1979 and 1985 were registered at the center. Patients have been closely followed up clinically and immunologically. OUTCOME MEASURES: Development of immunodeficiency, defined by a CD4 lymphocyte count falling beneath 0.20 and 0.05 x 10(9)/L, and death. RESULTS: Kaplan-Meier estimates suggest that almost half (46%; 95% confidence interval [CI], 26% to 66%) of patients alive 12 years after seroconversion will have a CD4 lymphocyte count that has remained above 0.05 x 10(9)/L. Thirty-five percent (95% CI, 22% to 48%) remain above 0.20 x 10(9)/L. Thirty-seven patients died of HIV-related causes, and there was a 52% probability (95% CI, 35% to 69%) of HIV-related mortality by 12 years from seroconversion. Mortality risk was closely associated with severe immunodeficiency. There was only a 15% chance (95% CI, 6% to 25%) of HIV-related death occurring before a CD4 count of below 0.05 x 10(9)/L had been reached. There was an average of one HIV-related death per 96.7 patient-years of observation before the CD4 count had fallen below 0.05 x 10(9)/L, as compared with one death per 2.5 patient-years of observation after the CD4 count had fallen below this level (P < .0001). CONCLUSIONS: In patients with HIV infection who are closely followed up, the risk of death is low before the CD4 lymphocyte count has fallen to 0.05 x 10(9)/L, a count many patients remain above up to 12 years after seroconversion.

CD4-Positive T-Lymphocytes↗
PubMed1992

Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis.

With the advent of standard flow cytometric methods using two-colour fluorescence on samples of whole blood, it is possible to establish the ranges of CD3, CD4 and CD8 T lymphocyte subsets in the routine laboratory, and also to assist the definition of HIV-1-related deviations from these normal values. In 676 HIV-1-seronegative individuals the lymphocyte subset percentages and absolute counts were determined. The samples taken mostly in the morning. The groups included heterosexual controls, people with various clotting disorders but without lymphocyte abnormalities as well as seronegative homosexual men as the appropriate controls for the HIV-1-infected groups. The stability of CD4% and CD8% values was demonstrated throughout life, and in children CD4 values less than 25% could be regarded as abnormal. The absolute counts of all T cell subsets decreased from birth until the age of 10 years. In adolescents and adults the absolute numbers (mean +/- s.d.) of lymphocytes, CD3, CD4 and CD8 cells were 1.90 +/- 0.55, 1.45 +/- 0.46, 0.83 +/- 0.29 and 0.56 +/- 0.23 x 10(9)/l, respectively. In patients with haemophilia A and B the mean values did not differ significantly. In homosexual men higher CD8 levels were seen compared with heterosexual men and 27% had an inverted CD4/CD8 ratio but mostly without CD4 lymphopenia (CD4 less than 0.4 x 10(9)/l). However, some healthy uninfected people were 'physiologically' lymphopenic without having inverted CD4/CD8 ratios. When the variations 'within persons' were studied longitudinally over a 5-year period, the absolute CD4 counts tended to be fixed at different levels. As a marked contrast, over 60% of asymptomatic HIV-1+ patients exhibited low CD4 counts less than 0.4 x 10(9)/l together with inverted CD4/CD8 ratios. Such combined changes among the heterosexual and HIV-1-seronegative homosexual groups were as rare as 1.4% and 3%, respectively. For this reason, when the lymphocyte tests show less than 0.4 x 10(9)/l CD4 count and a CD4/CD8 ratio of less than unity, the individuals need to be investigated further for chronicity of this disorder, the signs of viral infections such as HIV-1 and other causes of immunodeficiency.

Adolescent↗
PubMed1992

Sympathoadrenal stimulation, not endothelin, plays a role in acute pressor response to cyclosporine in anesthetized rats.

The possible role of sympathoadrenal stimulation and endothelin release in cyclosporine (CS)-induced hypertension was ascertained in intact and pithed rats. CS (20 and 40 mg/kg), administered by i.v. infusion over 10 min, produced a dose-dependent increase in blood pressure: 19 +/- 5 and 31 +/- 2 mm Hg in intact rats and 13 +/- 4 and 18 +/- 2 mm Hg in pithed rats. In intact rats, pretreatment with reserpine (5 mg/kg, i.p.) or hexamethonium (10 mg/kg, i.v.) greatly blunted the pressor responses to CS (40 mg/kg) (7 +/- 3 and 11 +/- 2 mm Hg, respectively). In pithed rats, the blood pressure responses to CS (40 mg/kg) were significantly impaired, but were not further modified by phenoxybenzamine (3 mg/kg, i.v.), whereas adrenalectomy completely abolished the CS-induced pressor responses (0 +/- 1 mm Hg). CS (40 mg/kg) did not potentiate pressor responses to sympathetic nerve stimulation (0.1 and 0.3 Hz) or vasoconstrictors, including angiotensin II (0.03 microgram/kg, i.v.), phenylephrine (1 microgram/kg, i.v.) and arginine vasopressin (0.075 microgram/kg) in pithed rats. In addition, CS (40 mg/kg, i.v.) did not cause elevation of plasma immunoreactive endothelin-1 and -3. Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension. It is concluded that the acute blood pressure response to CS manifests great dependence on sympathetic nervous system but appears independent of endothelin release.

Animals↗
PubMed1987

Antihypertensive, hemodynamic and autonomic profile of a new angiotensin converting enzyme inhibitor, SCH 33844 (spirapril).

SCH 33844 is a new, potent and long-acting inhibitor of angiotensin converting enzyme (ACE). Antihypertensive, hemodynamic and autonomic actions of SCH 33844 were examined in the present series of experiments. Oral administration of 0.3-30 mg/kg reduced blood pressure of spontaneously hypertensive rats. The magnitude of the response was significantly enhanced by pretreatment of the animals with hydrochlorothiazide. Blood pressure remained significantly depressed 24 hr following doses of 3 and 10 mg/kg. Administration of SCH 33844 (3 mg/kg) twice daily to nonpretreated rats or once daily to diuretic-pretreated animals for 5 days resulted in a progressive decrease in blood pressure. The compound did not reduce blood pressure in nephrectomized rats demonstrating the dependence of its action on renal renin. SCH 33844 (1-10 mg/kg orally) also produced dose-related decreases in pressure in diuretic-pretreated conscious normotensive dogs. However, only a small fall in pressure occurred in non-pretreated dogs. Hemodynamic actions were examined in anesthetized dogs. SCH 33844 (1 mg/kg i.v.) reduced blood pressure, increased cardiac output and caused a large fall in peripheral resistance. Autonomic actions were assessed in pithed rats. The compound (10 mg/kg orally) tended to decrease pressor responses to sympathetic activation and to i.v. norepinephrine. This profile is probably due, at least in part, to vasorelaxation following suppression of angiotensin II generation. In conclusion, SCH 33844 is a potent, long-lasting antihypertensive agent which reduces peripheral vascular resistance and possesses only slight autonomic effects.

Adrenergic Agonists↗
PubMed1987

Angiotensin converting enzyme inhibitory activity of SCH 33844 (spirapril) in rats, dogs and monkeys.

SCH 33844 is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of the synthetic substrate hippuryl-histidyl-leucine by rabbit lung ACE in vitro with an IC50 (concentration inhibiting enzyme by 50%) of 0.81 nM. The ester was 83 times less active. Intravenous administration of SCH 33844 and its diacid inhibited pressor responses to angiotensin I (AI) in anesthetized rats with calculated ID50's of 16 and 8 micrograms/kg, respectively. Oral administration of SCH 33844 (0.03-1 mg/kg) inhibited AI pressor responses in conscious rats with a duration of 24 hr at the highest dose. The diacid was inactive. Intravenous administration of SCH 33844 (100-1000 micrograms/kg) or its diacid (30 micrograms/kg) to anesthetized dogs inhibited AI pressor activity and potentiated the depressor response to bradykinin. SCH 33844 inhibited AI responses in conscious dogs following oral administration of 0.3-3 mg/kg. Oral administration of SCH 33844 (1 mg/kg) to conscious monkeys inhibited AI pressor responses for the 4 hr duration of study. In conclusion, SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys.

Angiotensin I↗
PubMed1986

Analysis of vascular responses in rat hindquarters arterial resistance vessels and veins in situ.

The venous compartment plays a critical role in circulatory control. The present series of experiments was conducted to assess simultaneously effects of vasoactive drugs on arterial resistance and venous capacitance vessels of the rat hindquarters perfused with physiological salt solutions (SS). Retrograde infusion of SS into rat hindquarters via the vena cava resulted in an increase in hindquarters venous pressure (Pv). The range of mean volumes required to increase Pv to 20 and 30 mm Hg was 1.7 +/- 0.1 to 2.9 +/- 0.4 and 3.8 +/- 0.3 to 6.9 +/- 0.3 ml, respectively, in various groups of rats during a control period. Perfusion of the hindquarters with an SS containing 80 mM K+ reduced the volume required to increase Pv to 20 and 30 mm Hg to 47 +/- 2 and 42 +/- 2% of control, respectively, indicating venoconstriction. K+ (80 mM) SS also increased aterial perfusion pressure (Pa; measured from a sidearm off of the inflow catheter) to 141 +/- 9 mm Hg, indicating arterial vasoconstriction. Arterial and venous responses to 80 mM K+ were attenuated markedly by perfusion with SS containing zero Ca and 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, indicating dependence on extracellular Ca. Phentolamine (10(-5) M) attenuated the arterial and venous response to 80 mM K+, indicating an alpha adrenergic contribution. Arterial responses to 80 mM K+ were attenuated markedly by the Ca entry blockers nifedipine (10(-6) and 10(-5) M) and verapamil (10(-6) and 10(-5) M). In contrast, venous responses were not affected by nifedipine and were reduced slightly only at the high concentration of verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Recovery and perturbation of paw-shake responses in spinal cats.

Paw-shake responses (PSRs) were evoked by wrapping masking tape around the hind-paw in nine cats spinalized at the T12 level either at 2 or 12 wk of age or as young adults (10-12 mo). Electromyographic responses of ankle extensors (LG and SOL) and one ankle flexor (TA) were recorded through the 6th mo after cord transection. Activity of the LG was used to determine the cycle characteristics. Cycle characteristics did not differ among cats spinalized at different ages. The average PSR, consisting of 11 cycles with a cycle time of 85 ms, was similar to the PSR of normal adult cats (16). Activity in the TA and LG muscles alternated with the onset of the flexor burst occurring at 52% of the extensor cycle. Burst durations averaged 39 and 57 ms for LG and TA muscles, respectively. Relatively normal PSRs were evoked within 48 h following cordotomy of the young-adult cats; differences being that the responses were elicited less frequently with fewer and slightly longer cycle times than normal. Within 2 wk following cord transection, PSR parameters returned to normal values. In the spinal cats, the SOL was active during PSR, showing either tonic low-level activity or discrete bursts that were coactive with the LG. In normal adult cats, the slow extensor (SOL) is usually inactive (16). In spinal cats, participation of the SOL may depend on a conversion of muscle units from slow to fast contracting (8, 13) or on the absence of inhibition of slow motor units from descending tracts (11). Both mechanisms are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1983

Enkephalinase 'A' inhibition by thiorphan: central and peripheral cardiovascular effects.

On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on responses to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of [D-Ala2,Met5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 micrograms i.c.v.) potentiated the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30-40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkephalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.

Amino Acids, Sulfur↗
PubMed1981

Comparison of hypotensive, orthostatic and sympathetic inhibitory actions of antihypertensive drugs in rats.

Hypotensive and orthostatic activities of a variety of orally administered antihypertensive drugs were concurrently evaluated in conscious spontaneously hypertensive rats and attempts were made to relate these responses to effects on peripheral sympathetic function. The alpha-adrenergic blockers phentolamine and prazosin and the adrenergic neuron blocker guanethidine inhibited compensatory responses to upright tilt at antihypertensive doses. The ganglionic blocker mecamylamine produced milder inhibition. The centrally active agents methyldopa and clonidine and the vasodilator minoxidil did not alter tilt responses appreciably. In contrast, the vasodilator hydralazine exerted marked postural effects. Autonomic interactions were evaluated in pithed rats. alpha-Adrenergic receptor, adrenergic neuron and ganglionic blockers inhibited pressor responses to i.v. phenylephrine and/or to sympathetic nerve activation. Vasodilators did not produce specific effects. The tilt and pithed rat models, when used in conjunction, are very useful in predicting orthostatic potential of drugs in humans although absolute correlation cannot be expected.

Animals↗