Short-acting Formulations Research Articles

Current position of calcium antagonists in hypertension.

Periodically in the history of antihypertensive therapy, minor storms have significantly affected the use of entire classes of agents. An early example is the publication of case-control studies suggesting that reserpine was associated with increased risk of carcinoma of the breast, a claim subsequently disproved by a number of other studies. A new controversy has developed recently with the publication of a case-control study report and a non-randomized cohort study which have questioned the use of calcium antagonists in hypertension. The case-control study suffers from the same disadvantages as the reserpine report and, indeed, another case-control study published in 1995, though not so well publicized, reached exactly opposite conclusions, claiming that calcium antagonists were significantly less associated with myocardial infarction than traditional antihypertensive therapy. A meta-analysis has also been presented in support of the non-randomized studies questioning the safety of calcium antagonists. However, this study refers to patients with coronary heart disease, not to patients with hypertension, and also suffers from lumping studies performed with different aims and using data from short-term and long-term studies on short-acting formulations of calcium antagonists. The controversy generated by these reports has gone well beyond their scientific merit. Well designed prospective studies are needed, and several of these are under way at present. For the time being there is no reason to change the current practice of antihypertensive therapy, as summarized in the recommendations of both the United States Joint National Committee and the World Health Organization/International Society of Hypertension Committee, that diuretics and beta-blockers are among those antihypertensive agents with more clearly proven benefit on the basis of mortality-morbidity studies, while calcium antagonists, angiotensin converting enzyme inhibitors and alpha-blockers can also be profitably used in the treatment of hypertension.

Primary prevention of coronary heart disease in hypertension.

MORTALITY FROM MYOCARDIAL INFARCTION: Primary prevention of coronary heart disease in hypertension is important because the mortality among those who have suffered a myocardial infarction is around 50% within 1 month of the infarction. Although the mortality of those who reach hospital has about halved over the last decade (to about 8%), prevention is the only way to affect coronary mortality overall. OVERALL PREVENTION OF CORONARY HEART DISEASE: There are several proven strategies, involving both drugs and lifestyle changes. Stopping smoking is the most powerful, but exercise and reduction of dietary fats and salt are also important; the latter will need co-operation with the food industry. TREATING HYPERTENSIVES WITH A CORONARY RISK: Lipid-lowering drugs will be needed for some, but not all hypertensives, depending on the coronary risk. Some drug treatments which lower blood pressure (e.g. short-acting formulations of nifedipine) may not reduce the coronary risk; further data or newer preparations are awaited. Potassium-sparing diuretics (particularly in elderly patients) and/or beta-blockers remain the first choice for primary prevention. If a calcium channel blocker is needed, verapamil or diltiazem are useful in patients with no left ventricular dysfunction.

Calcium antagonists during and after myocardial infarction.

Calcium antagonists, or calcium channel entry blockers, have been advocated as cardioprotective agents in acute myocardial infarction (AMI) on the basis of animal experiments, which show that they will reduce the harmful effects of the calcium overload which follows ischaemia, particularly during reperfusion, and also that they will reduce coronary artery spasm. Unfortunately, these promising actions have not translated into clear mortality data. An overview of the large amount of data from properly randomised controlled clinical trials shows clear differences between the dihydropyridine class of calcium antagonists such as nifedipine, and the non-dihydropyridines verapamil and diltiazem. Most of the data with the former group derive from trials with short-acting formulations of nifedipine (TRENT, HINT, SPRINT-I and -II). Overall, none of these trials showed significant benefit in either AMI or post-MI prophylaxis. There was a trend for harm, with HINT stopped early because of excess reinfarction with nifedipine, compared with metoprolol. In contrast, and when taken together, the DAVIT-I and DAVIT-II studies with verapamil show significant reductions in sudden death, reinfarction and total mortality. The greatest benefit occurred in those patients with relatively good left ventricular function. Similar but less significant trends were seen in studies with diltiazem. It is clear that calcium antagonists, unlike beta-blockers, cannot be treated as a similar class. It seems likely that the adverse effects of nifedipine are related to reflex sympathetic cardiac stimulation as a result of the predominantly vasodilator action of these dihydropyridine compounds. Data on newer dihydropyridines with fewer reflex effects are awaited. In the meantime it seems sensible to use proven agents such as beta-blockers or verapamil. These data on AMI and the months following have recently been paralleled by case control studies in hypertension, which similarly have suggested harm from the use of predominantly short acting formulations of nifedipine compared with beta-blockers and which led to a warning statement by the US National Heart, Lung, and Blood Institute on 1 September 1995.

Relevance of 24 H blood pressure profile and sympathetic activity for outcome on short- versus long-acting 1,4-dihydropyridines.

Short-acting formulations of nifedipine-like 1,4-dihydropyridines cause clearly less regression of left ventricular hypertrophy (LVH) than anticipated from their antihypertensive effect. Moreover, these compounds increase the risk of cardiac death and myocardial reinfarction in patients with coronary artery disease (CAD) not on concomitant beta-blocker therapy. Increased sympathetic activity is one of the non-pressure-related risk factors for LVH and atherosclerosis in hypertensives. In addition, increased sympathetic tone may precipitate clinical events in subclinical or stable CAD. Intermittent increases in sympathetic activity persist during chronic treatment with those 1,4-dihydropyridines that have a poor peak/trough ratio with a rapid fall of BP and deactivation of the arterial baroreflex. On the other hand, these intermittent increases in sympathetic activity do not occur for formulations and compounds with a gradual and sustained antihypertensive effect over the dosing interval. Such long-acting 1,4-dihydropyridines cause regression of LVH as anticipated from their antihypertensive effect, and are similar to angiotensin converting enzyme inhibitors. In contrast to short-acting 1,4-dihydropyridines, long-acting 1,4-dihydropyridines appear not to be detrimental for patients with stable CAD. However, the evidence is still missing for patients with unstable CAD. Neither is there evidence that they will reduce cardiovascular morbidity and mortality in patients with CAD when used for the chronic treatment of hypertension.

Nifedipine and Mortality

When an approved treatment is considered for an unapproved indication, the physician must evaluate the safety of the medication, its value in related conditions, and the individual patient. What is asked is that he make a prudent decision based upon full knowledge of the available evidence.”1 Furberg and his colleagues2 entitle their article “Nifedipine: Dose-Related Increase in Mortality in Patients With Coronary Heart Disease.” They provide a valuable service by making us think more carefully about the benefit/risk ratio of the calcium antagonists as a group. However, by touting calcium antagonists as being unsafe and possibly lethal, they also create a great deal of uncertainty and anxiety among physicians and patients. We feel that they overstate their case. The following is an attempt to show that (1) the allegations focus on short-acting nifedipine, so that even if correct, they cannot be applied to other calcium antagonists; (2) the accusation of a dose-related increase in mortality rests on a biased selection of data chosen for the meta-analysis; and (3) several of the mechanisms suggested for the proposed adverse effects are unlikely. Finally, we shall argue that pharmaceutical companies have been remiss in not obtaining outcome studies for short-acting nifedipine and for other calcium antagonists, especially in the case of ischemic heart disease. Several aspects of the Furberg paper suggest that calcium antagonists in general are accused; for example, the statement that “the literature reviews strongly suggest that the problem may go beyond short-acting nifedipine. Troubling and major adverse cardiovascular events have been linked to other calcium antagonists, primarily dihydropyridines.” It should be clearly and unequivocally stated that Furberg et al2 provide no evidence whatsoever for any adverse effect on mortality or morbidity for any other agent, with one important exception. That exception is nimodipine, approved for use in …

Antiuterotrophic effects of a pure antioestrogen, ICI 182,780: magnetic resonance imaging of the uterus in ovariectomized monkeys

ICI 182,780 is a potent specific pure antioestrogen which may offer advantages in breast cancer treatment compared with partial agonists like tamoxifen. To characterize further the potency and efficacy of ICI 182,780, its effects on the uterus of ovariectomized, oestrogen-treated monkeys (Macaca nemestrina) have been measured using magnetic resonance imaging (MRI). Quantitative MRI allows accurate non-invasive repetitive measurements of endometrial and myometrial volume following hormonal treatments, using each animal as its own control. Single i.m. injections of a long-acting oil-based formulation of ICI 182,780 sustained blockade of oestradiol action on the monkey uterus in a dose-dependent manner for 3-6 weeks. Repeated injections of 4 mg ICI 182,780/kg at 4-weekly intervals provided increasingly effective blockade of uterine proliferation. In a short-acting formulation, ICI 182,780 also completely blocked the trophic action of oestradiol, administered concurrently, in ovariectomized monkeys. Similarly, ICI 182,780 caused involution of the uterus stimulated by prior treatment with oestradiol. The rate and extent of uterine involution in monkeys treated with ICI 182,780 was similar to that seen following oestrogen withdrawal. These studies demonstrate that ICI 182,780 is a fully effective pure antioestrogen in a primate.

Further evaluation of the use of buparvaquone in the infection and treatment method of immunizing cattle against Theileria parva derived from African buffalo ( Syncerus caffer)

Three experiments were undertaken to determine the efficacy of different doses of buparvaquone in the infection and treatment immunization of cattle against Theileria parva derived from African buffalo ( Syncerus caffer). Two of these experiments also compared buparvaquone with standard doses of long- and short-acting formulations of oxytetracycline. In addition, different dilutions of stabilates were used in the experiments. In the first experiment, a 10 −1.0 dilution of stabilate was used to infect groups of cattle treated with buparvaquone at doses of between 5 and 0.625 mg kg −1 body weight (bwt) on Day 0 after infection. All control cattle developed severe theileriosis and none of the treatment regimes (including those utilizing long-active oxytetracycline) prevented the development of theileriosis. Treatment with buparvaquone at 2.5 mg kg −1 bwt or oxytetracycline gave the most satisfactory results. In the second experiment when the sporozoite dose was reduced to 10 −2.0 dilution, buparvaquone treatment at 5 and 2.5 mg kg −1 bwt and short- and long-acting formulations of oxytetracycline reduced reactions greatly. While all the oxytetracycline treated animals produced a serological response and were immune to a 50-fold higher challenge with the immunizing stabilate, several animals in the buparvaquone groups did not show a serological response and were not immune to challenge. In the third experiment, groups of cattle were infected with 10 −1.2, 10 −1.4 and 10 −1.6 dilutions of stabilate and were treated with 2.5 mg kg −1 bwt of buparvaquone. No animals developed severe theileriosis and all seroconverted. On homologous challenge, however, two out of 14 cattle showed severe reactions. It was concluded that further work on immunization using buparvaquone treatment at 2.5 mg kg −1 bwt and 10 −1.6 dilution of the stabilate would have to be carried out before such a system could be used in the field.

Immunisation of cattle against theileriosis in Nakuru District of Kenya by infection and treatment and the introduction of unconventional tick control

One hundred and one cross European-Boran cattle (50 cows and 51 calves), on a farm in Nakuru District, Kenya, were immunised against theileriosis using Theileria parva lawrencei and Theileria parva parva stocks from another district of Kenya. The stabilates used were T.p.lawrencei (Mara III) used at 10 −1.7 dilution and T.p.parva (Kilae) used at 10 −1.0 dilution. The stabilates were combined and inoculated simultaneously with a short-acting formulation of oxytetracycline hydrochloride given intramuscularly at 10 mg kg −1 body weight and was repeated on Day 4 after inoculation of the stabilate. Most of the theileriosis challenge on the farm was thought to be derived directly from the African buffalo ( Syncerus caffer). Nine percent of the cattle had significant indirect fluorescent antibody (IFA) titres before the immunisation and 99% after immunisation. The immunised cattle were exposed to tick-borne disease challenge on the farm by withdrawal of acaricide cover. The immunised cattle were divided into five groups plus two susceptible control cows and two calves for each group. Cattle in four of the groups had acaricidal ear tags, each group having a different type, applied to both ears and the fifth group remained untagged. The animals remained without conventional acaricide application for 134 days. Ten out of 20 (50%) non-immunised control cattle became T.p.lawrencei reactors while only one out of 97 (1%) of the immunised cattle reacted. A frequent complication noted was mild infections due to unidentified Theileria sp. which required expert differentiation from T.parva infections. An additional group of ten steers whose tick load was removed by hand at weekly intervals was introduced 79 days after exposure; these had no tick control and four became T.p.lawrencei reactors. Of 12 calves born during the exposure period and without tick control, four became theilerial reactors and one died. The application of acaricidal tags however, reduced tick infestation levels considerably compared with untagged controls but did not prevent transmission of theileriosis with the possible exception of tags on Group 4. A number of transient low grade fevers were noted and attributed to Theileria sp., Ehrlichia bovis, Ehrlichia (Cytoecetes) ondiri and Borrelia theileri infections, none of which were fatal. One immunised animal died of acute dual infection of Babesia bigemina and Borrelia theileri after acaricide control by spraying was re-introduced but no Anaplasma infections were detected. An analysis of the economic effects of immunisation was made.

Evaluation of infection and treatment methods in immunization of improved cattle against theileriosis in an endemic area of Kenya

Five experiments were carried out to determine the efficacy of immunization against theileriosis in an endemic area of Kenya using artificial infection with a mixture of stabilates of Theileria parva stock or natural infection and treatment with parvaquone or several formulations of oxytetracyclines. For the first four experiments, introduced, susceptible Sahiwal/Friesian crosses were used and in the fifth, calves of Boran/Maasai zebu crosses born on the site. Cattle were infected either artificially with sporozoite stabilates of local isolates of T. parva parva derived from cattle and T. parva lawrencei derived from African buffalo or exposed to natural tick challenge on the ranch mostly derived from buffalo. The cattle were then given various treatment regimens using either parvaquone or long- and short-acting formulations of oxytetracycline. Treatment of natural infections, although it can be effective, was not considered a practical method on a large scale because of the need for intensive monitoring in the case of parvaquone treatment and the possibility of cattle not becoming infected in the case of prolonged application of long-acting formulations of oxytetracycline. Both methods were relatively expensive. Artificial infection treatment proved more practical and methods were developed where the monitoring of cattle was not required during the immunization procedure. Out of a total of 16 drug regimens investigated, one (consisting of two treatments of a short-acting formulation of oxytetracycline at 10 mg kg −1 body weight on Days 0 and 3 or 4 after infection) was found to be the most efficacious and the cheapest, and has now been used on a routine basis. This method can be used successfully on calves >1 month of age.

Theilerial parasites isolated from carrier cattle afterimmunization withTheileria parvaby the infection and treatment method

Groups of cattle were immunized with 10−2dilutions of sporozoite stabilates ofTheileria parva lawrenceiderived from African buffaloes either alone or in combination withTheileria parva parvaderived from cattle and concomitant treatment with either long or short-acting formulations of oxytetracyline. At 90 or 120 days after infection, uninfectedRhipicephalus appendiculatusnymphal ticks were applied to individual immunized cattle and the resultant adults ticks were applied to individual susceptible cattle. Theilerial infection developed from ticks fed on 6 out of 11 animals investigated for evidence of a carrier state. Two additional animals were shown by cell-culture isolation to have persistent theilerial infections. Nine cattle infected with the parasites from carrier animals were treated with parvaquone and 7 recovered. These recovered cattle were then challenged with the original immunizing stabilates at 10° dilution together with the original immunized and carrier cattle. Six out of 7 cattle which had recovered from carrier-derived infection succumbed to this challenge and died but none of the original immunized cattle showed theilerial reactions. When a carrier-derived sporozoite stabilate was used to challenge cattle immune to the original immunizing parasite, they proved to be immune. Cattle immune to the carrier-derived parasites were all immune to challenge with the original parasite. A monoclonal antibody profile aginstT. parvaschizonts isolated by cell culture from samples of the experimental animals did not appear to be sensitive enough to determine the antigenic differences between the carrier-derived parasite and the original immunizing parasite. Indications are that the carrier state is not likely to produce new antigenic strains which would be dangerous to immunized cattle.

Theilerial parasites isolated from carrier cattle after immunization with Theileria parva by the infection and treatment method

Groups of cattle were immunized with 10(-2) dilutions of sporozoite stabilates of Theileria parva lawrencei derived from African buffaloes either alone or in combination with Theileria parva parva derived from cattle and concomitant treatment with either long or short-acting formulations of oxytetracyline. At 90 or 120 days after infection, uninfected Rhipicephalus appendiculatus nymphal ticks were applied to individual immunized cattle and the resultant adults ticks were applied to individual susceptible cattle. Theilerial infection developed from ticks fed on 6 out of 11 animals investigated for evidence of a carrier state. Two additional animals were shown by cell-culture isolation to have persistent theilerial infections. Nine cattle infected with the parasites from carrier animals were treated with paravaquone and 7 recovered. These recovered cattle were then challenged with the original immunizing stabilates at 10 degrees dilution together with the original immunized and carrier cattle. Six out of 7 cattle which had recovered from carrier-derived infection succumbed to this challenge and died but none of the original immunized cattle showed theilerial reactions. When a carrier-derived sporozoite stabilate was used to challenge cattle immune to the original immunizing parasite, they proved to be immune. Cattle immune to the carrier-derived parasites were all immune to challenge with the original parasite. A monoclonal antibody profile against T. parva schizonts isolated by cell culture from samples of the experimental animals did not appear to be sensitive enough to determine the antigenic differences between the carrier-derived parasite and the original immunizing parasite. Indications are that the carrier state is not likely to produce new antigenic strains which would be dangerous to immunized cattle.

Immunization of cattle against theileriosis using varying doses of Theileria parva lawrencei and T. parva parva sporozoites and oxytetracycline treatments

Mutugi J.J., Young A. S., Maritim A. C., Udungu S. G., Stagg D. A., Grootenhuis J. G. and Leitch B. L. 1988. Immunization of cattle against theileriosis using varying doses of Theileria parva lawrencei and T. parva parva sporozoites and oxytetracycline treatments. International Journal for Parasitology 18: 453–461. Theileria parva lawrencei and T. parva parva parasites, from three sources (two from African buffalo, Syncerus caffer, and one from indigenous cattle, Bos indicus) isolated from two areas of Kenya, were chosen for investigations into immunization of cattle against theileriosis. Varying concentrations of stabilates were used to infect cattle singly in one experiment and in combination in another experiment, with one or two treatments with either long- or short-acting formulations of oxytetracyclines, respectively. It was found that high concentrations with T. parva lawrencei stabilates (10°) were not controlled satisfactorily by oxytetracyclines but with concentration of stabilate at 10 −1 or particularly 10 −2 it was possible to induce sub-clinical theileriosis with the development of antibodies to T. parva. Both short- and long-acting formulations of oxytetracyclines appeared to be equally effective. Some chronic effects were seen after immunization but these were not usually detected when lower concentrations of stabilate were given. Cattle immunized by this procedure were shown to be immune to homologous and heterologous challenge and some were demonstrated to become T. parva carriers.

Tolerance to organic nitrates in ischemic heart disease.

The development of tolerance to organic nitrates in patients with ischemic heart disease is reviewed, with particular interest in alterations to both the hemodynamic and antiischemic effects over time. The article primarily focuses on how tolerance is defined, what biochemical mechanisms are involved when this condition occurs, which agents have been associated with the development of tolerance, and what can be done to prevent or reverse the condition in patients taking nitrates for ischemic heart disease. From a historical perspective, tolerance to organic nitrates has been a recognized phenomenon since the last century. The role that blood-level determinations and nitroglycerin pharmacokinetics have in the development of tolerance is discussed, and an extensive overview of currently marketed organic nitrate preparations and a few others available only through approved investigational protocols is presented. The role of cross-tolerance is discussed as is the role that nitrate-free intervals play in partially or completely reversing the effects of tolerance during chronic nitrate therapy. Additionally, a discussion of which specific nitrate formulation are least likely to have tolerance associated with their use is included, such as short-acting nitrate formulations with the exception of the intravenous dosage form. Finally, buccal nitroglycerin is presented as another new formulation that appears to be associated with minimal tolerance in studies already completed.

Gram-negative shock.

The conception of septic shock as essentially an inadequate capillary perfusion is offered. Though cardiac output may be high the inadequate perfusion apparently a paradox is explained by the opening of many arteriovenous shunts simultaneously with arteriolar vasoconstriction. In addition to the vasoconstriction capillaries are obstructed completely in many cases by microthrombi secondary to disseminated intravascular coagulation. When the endotoxin is liberated in the bloodstream it is selectively taken up by platelets which immediately agglutinate and dissapear from the bloodstream. With the breakdown of platelet thrombi thromboplastin is liberated from the platelets which initiates the fibrinogen to fibrin reaction resulting ultimately in incoagulable blood. Treatment theories presented all have in common the belief that maximum expansion of the blood volume should be carried out before any attempt at treatment by vasoactive drugs is made. Vasoactive drugs should be administered only after failure of antibiotics indicated surgery adequate volume administration oxygen respiratory assistance correction of electrolyte balance and other supportive measures. Sympathomimetic drugs include alpha-stimulating agents which are characterized by 2 actions: inotropic effect on the heart and peripheral arterial vasoconstriction (the author warns against their use); beta-stimulating agents such as isoproterenol which cause peripheral vasodilation but also stimulate the heart (contraindicated with a pulse rate of more than 100); and alpha-blocking agents which in the long acting forms actually kill the sympathetic nerve endings temporarily or in short-acting forms require intravenous drip administration to regulate the level of vasodilation. The onset of incoagulability of blood denotes the onset of disseminate intravascular coagulation; though vasodilators may be useful in improving flow and preventing disseminated intravascular coagulation the best treatment would be rapid administration of whole blood for the condition really results from depletion of clotting factors.

Iron pyriets and calamine

One hundred and one cross European-Boran cattle (50 cows and 51 calves), on a farm in Nakuru District, Kenya, were immunised against theileriosis using Theileria parva lawrencei and Theileria parva parva stocks from another district of Kenya. The stabilates used were T.p.lawrencei (Mara III) used at 10−1.7 dilution and T.p.parva (Kilae) used at 10−1.0 dilution. The stabilates were combined and inoculated simultaneously with a short-acting formulation of oxytetracycline hydrochloride given intramuscularly at 10 mg kg−1 body weight and was repeated on Day 4 after inoculation of the stabilate. Most of the theileriosis challenge on the farm was thought to be derived directly from the African buffalo (Syncerus caffer).Nine percent of the cattle had significant indirect fluorescent antibody (IFA) titres before the immunisation and 99% after immunisation. The immunised cattle were exposed to tick-borne disease challenge on the farm by withdrawal of acaricide cover. The immunised cattle were divided into five groups plus two susceptible control cows and two calves for each group. Cattle in four of the groups had acaricidal ear tags, each group having a different type, applied to both ears and the fifth group remained untagged. The animals remained without conventional acaricide application for 134 days. Ten out of 20 (50%) non-immunised control cattle became T.p.lawrencei reactors while only one out of 97 (1%) of the immunised cattle reacted. A frequent complication noted was mild infections due to unidentified Theileria sp. which required expert differentiation from T.parva infections.An additional group of ten steers whose tick load was removed by hand at weekly intervals was introduced 79 days after exposure; these had no tick control and four became T.p.lawrencei reactors. Of 12 calves born during the exposure period and without tick control, four became theilerial reactors and one died. The application of acaricidal tags however, reduced tick infestation levels considerably compared with untagged controls but did not prevent transmission of theileriosis with the possible exception of tags on Group 4. A number of transient low grade fevers were noted and attributed to Theileria sp., Ehrlichia bovis, Ehrlichia (Cytoecetes) ondiri and Borrelia theileri infections, none of which were fatal. One immunised animal died of acute dual infection of Babesia bigemina and Borrelia theileri after acaricide control by spraying was re-introduced but no Anaplasma infections were detected. An analysis of the economic effects of immunisation was made.