New drug sugammadex: a selective relaxant binding agent.

Cyclodextrins are molecules with a hollow, truncated cone shape that possess unique lipophilic and hydrophilic properties. These unique properties enable cyclodextrins to engulf and bind lipophilic molecules while maintaining aqueous solubility. Encapsulation of molecules is the principal action of a new drug class, selective relaxant binding agents, which binds and inactivate aminosteroid nondepolarizing muscle relaxants. Sugammadex is the name of a modified cyclodextrin currently in phase 3 studies by Organon International (Oss, The Netherlands), and it may hold promise for a new concept in muscle relaxant reversal. Encapsulation rather than competitive antagonism of neuromuscular blockade may be a future modality of anesthetic practice.

Clinical evaluation of a new oral contraceptive, 'Pregnon'.

'Pregnon', a new oral contraceptive containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol, was administered cyclically to 639 women of fertile age over a total of 9,159 cycles. There were no pregnancies. In most cases the withdrawal bleeding resembled normal menstruation. The incidence of metrorrhagia was relatively low and when it did occur it was usually confined to the early treatment cycles and was of very limited duration. The objective and subjective tolerance was excellent.

PIP: Pregnon is a new low-dosage ovulation-inhibiting agent containing 1 mg of lynestrenol and .05 mg of ethinyl estradiol in each tablet. It is also marketed under the name of Pregnon 28 or Ovostat 28 in which each package contains 22 active plus 6 placebo tablets. Data were collected from Belgian clinics and evaluated by the Medical Unit of Organon in Belgium and the Netherlands. During this study, 639 women of fertile age were monitored through 9159 cycles. The maximum period of treatment was 36 cycles. Clinical and gynecological examinations were made before treatment and then every 2 or 3 months. Treatment was begun by taking the 1st tablet on the 1st day of menstruation. After taking 22 tablets there was a 6-day tablet-free interval during which withdrawal bleeding usually occurred. The intensity of the withdrawal bleeding was normal in 57.3%, slight in 41.7%, and heavy in 1%. Spotting was noted in 3.1% of the cycles and breakthrough bleeding occurred in 2.9%. Usually they occurred in the first 3 cycles. Amenorrhea was observed in 2.9% of the cycles. Body weights were relatively unchanged. Blood pressures remained the same. Side effects were headache, nausea, vomiting, breast tenderness, heavy legs, leucorrhea, nervousness, depression, and decreased libido. Only 46 patients discontinued treatment because of these drug effects yielding an acceptability level of about 93%. Since no pregnancies occurred during this study, the Pearl index was 0.

The safety and value of naloxone as a therapeutic aid.

The safety and value of naloxone as a therapeutic aid was demonstrated in a large population of narcotic dependent persons over a two-year period. Naloxone was used to precipitate the narcotic withdrawal syndrome. This withdrawal syndrome was rated according to a previously developed scale. Retrospectively, naloxone rating scores were correlated with the patients' initial dose of methadone. With patients who received 0.8 mg naloxone, good correlation was obtained between the naloxone test score and the optimum methadone dose (mg), as indicated by the patients' physical status during the initial three days of methadone treatment. Three hundred and sixty-three tests were administered to 343 persons and no individuals developed any serious effects such as convulsions, syncope or cardiovascular collapse.

Anecdotal therapies.

Traditionally, many advances in medicine have been serendipitous. Are serendipitous and anecdotal synonymous? Many of our materia medica today relate to initial probes and anecdotal reports that matured to full investigation and therapeutic indications. The recent situation regarding Skin Cap is one that highlights the downside of this scenario. Several drugs in the US continue usage largely related to anecdotal indications, and anecdotal extension of legend indications is a standard for American Dermatology. The situation with systemic drugs, such as Trental, zinc preparations, imidazoles for extended indications, lysine and melatonin, all will be discussed. Topical preparations such as skin cap, cantharone, Vioform, all also are included in this category. It is important to place this topic in perspective in regards to geographic variation and therapeutic need. Many diseases lacking specific therapy are important targets for anecdotal therapy, and this will foster continued approaches in this area. The growing standardization of medicine and pharmaceutical regulation, threatens the anecdotal approach, but it provides still an important link to the future for some forms of therapy in diseases that are difficult to treat. Traditionally, the anecdote has been the first step in the therapeutic chain. Withering discovery of the benefits of the common fox glove in dropsy, was followed by many other anecdotes arriving via folk-medicine in the New World. This approach of utilizing folk medicine has now reached new heights, with very active searches by major pharmaceutical companies throughout the third world for remedies that may have potential. Couched with this is the history of anecdotal "snake-oil" remedies, that clearly had no benefit to anyone except the huckster marketing same. The excesses in this area of unproven and false therapies, led to the gradual organization of therapeutic trials and the Food and Drug Administration in the US as we know it today. The biggest shot in the arm for enhancing FDA protocols was the thalidomide situation, an outgrowth of an ethically studied and used medication that perhaps had been released too soon, prior to sufficient trials to determine the total patient risk. As in many situations, the pendulum swings in both directions, and after thalidomide, the acceptance of new treatments required more and more rigorous studies, and studies from other countries often were not acceptable unless a small part of a larger, whole proposal. The AIDS crisis has prompted a swing back, away from such expensive and rigorous pre-marketing review, to more expedited processes for the relief of patients with this fatal disease. This has streamlined the FDA, and hopefully the swing of the pendulum will not go too far, to result in problems in the future. Anecdotal therapies and medications are the first step in many parts of the world to therapeutic trials. The most widely used aspects of anecdotal therapies, again, remains in the situation with diseases without good therapies at the present time. The so-called orphan drugs and orphan diseases, while a serious medical problem, do not present a significant volume for effective drug screening in many instances, and the FDA has developed some new approaches to circumvent this very expensive development process for patients suffering from these rare and unusual disorders. The most recent example of anecdotal therapy catching the public fancy in dermatology was the Skin-Cap Spray. This product, over the period of twelve months, got rave reviews in the lay press in the non-peer reviewed dermatologic periodicals, and amassed impressive sales figures in this period of time. It was extremely effective, and most dermatologists who used it have patients who consider it the most effective therapy in the last year. The formulation of a low concentration of zinc pyrithione seemed unusual, and this truly was an anecdotal approach, using a homeopathic dosage of a commonly used p

Randomized double-blind placebo-controlled trial of homoeopathic 'proving' for Belladonna C30.

Homoeopathic drug pictures are developed by recording the symptomatic effects of homoeopathic remedies given to healthy volunteers (a 'proving'). In a double-blind randomized controlled trial we tested the hypothesis that individuals using an infinitesimal dilution of Belladonna (thirtieth potency, C30) would record more true symptoms, on a questionnaire that contained both true and false Belladonna proving symptoms, than those receiving placebo. 60 volunteers entered the study and 47 completed data collection. We were unable to distinguish between Belladonna C30 and placebo using our primary outcome measure. For the secondary outcome measure we analysed the number of individuals who proved to the remedy according to our predefined criteria: 4 out of 19 proved in the Belladonna C30 group and 1 out of 27 in the placebo group (difference not statistically significant). This pilot study does not demonstrate a clear proving reaction for Belladonna C30 versus placebo, but indicates how the question might be further investigated.

Total intravenous anesthesia with etomidate. II. Evaluation of a practical technique for children.

A practical technique for the administration of anesthesia to children is described, using only intravenous agents. Anesthesia was induced using etomidate 0.3 mg/kg, analgesia being provided by fentanyl or pentazocine, and muscle relaxation by suxamethonium or pancuronium. Unconsciousness was maintained by infusion of a 1% solution of etomidate given at a pre-determined rate of 30 microgram/kg/min. Paralysis was maintained throughout the period of surgical stimulation, in the majority of patients by continuous infusion of suxamethonium 0.1 mg/kg/min. The chosen rate of infusion of etomidate appears to be adequate to reliably maintain sleep in children, yet allow rapid recovery of consciousness when the infusion is stopped, thereby relieving the anesthetist of concern about these points. The maintenance of complete paralysis throughout operation removes the possibility of movement, the major cause of unsatisfactory anesthesia using only intravenous agents.

Clinical experiences with naloxone in neuroradiology.

In 17 patients, the reversal by naloxone of a short duration narcotic anesthesia done for neuroradiology, was studied. Neuroleptanalgesic technique comprised d-hydrobenzperidol (5-10 mg) and fentanyl (+/- 0.4 mg) after barbiturate induction, and curarization with pancuronium, reversed by neostigmine. In group A 2 microgram/kg naloxone I.V. was given and 1 microgram/kg I.M. 30 min. later and in group B 1 micrometer/kg I.V. and 30 min. later 0.5 micrometer/kg. Reversal of narcotic depression was good and well maintained for 60 min. in both groups, as evidenced by respiratory rate, respiratory minute volume, pHa, PaCO2. Marginal temporarily cardiovascular stimulation occurred with arousal. Tolerance was good. It is concluded that antagonisation of respiratory depression due to narcotic anesthesia is possible with small titrated dosis of naloxone.

On a national drug policy for Bangladesh.

PIP: On April 27, 1982 the Ministry of Health of the government of Bangladesh, set up an 8-man expert committee to evaluate all the registered pharmaceutical products presently available, and to formulate a draft National Drug Policy. Objectives are: 1) to provide support for ensuring quality and availability of drugs; 2) to reduce drug prices; 3) to eliminate useless, nonessential, and harmful drugs from the market; 4) to promote local production of finished drugs; 5) to ensure coordination among government branches; 6) to develop a drug monitoring and information system; 7) to promote the scientific development and application of unani, ayurvedic, and homeopathic medicines; 8) to improve the standard of hospital and retail pharmacies; and 9) to insure good manufacturing practices. 16 criteria were agreed on as guidelines for evaluating the drugs on the country's market. Drugs in Bangladesh have been classified into 3 categories. The 1st is drugs that are positively harmful. They should be banned immediately and withdrawn from the market. There are 265 locally manufactured drugs and 40 imported drugs in this category. The 2nd, drugs to be slightly reformulated by eliminating some of their requirements. There are 134 drugs in this category. The 3rd is drugs that do not conform to 1 or more of the 16 criteria/guidelines. There are over 500 drugs in this category. The new drug policy will produce a saving of 800 million taka (US $32.4 million). Drug supply in Bangladesh is a problem. The public sector distributes 20% of the total. In the private sector, drugs are supplied through import and local production. Investment for research by the pharmaceutical companies is essential. The principles laid down by the International Federation of Pharmaceutical Manufacturers Associations for the supply of good medicine needs to be put into practice.^ieng

[Special therapeutic processes from the viewpoint of clinical pharmacology]. / Besondere Therapierichtungen aus der Sicht der Klinischen Pharmakologie.

Special therapies comprise homeopathic drugs, anthroposophic medicine and phytotherapy a heterogenous mixture, which consists partly on authorities (Hahnemann, Steiner) and partly describes the origin of the drug (herbal drugs). The field, therefore, is open to new additions (Chinese traditional medicine, American Indian drug therapy etc.). These drugs do not meet the requirements for safety and efficacy required for modern drugs and this is not required, because according to German lawyers this would be inadequate. We demonstrate examples where the health of patients has been severely damaged by this kind of medical therapies and point out that these problems continue. Reasons are presented, why the public has the right to demand proof of efficacy and safety of all drugs.

[Evaluation of the degree of muscle blockade: a comparative study using electromyography of the muscular relaxation induced by pancuronium, atracurium and vecuronium]. / Evaluación del grado de bloqueo muscular: estudio comparativo mediante electromiografía de la relajación muscular provocada por el pancuronio, atracurio y vecuronio.

To compare the muscle relaxing effect of pancuronium, atracurium and vecuronium, 99 patients operated on under neuroleptanesthesia were divided in three groups depending on whether they had received, during induction, pancuronium 0.1 mg/kg, atracurium 0.5 mg/kg, or vecuronium 0.1 mg/kg. One-fourth of the initial dose was repeated if necessary. The electromyographic study of the muscle relaxing effect was carried out with stimulation of the cubital nerve with courses of supramaximal square wave electric stimuli in 'trains of four'. The time to maximal blockade (TMB), the time of clinical effectiveness (TCE), the total duration time (TDT), the time of duration of the maintenance dose (DM 25) and the recovery index (RI) were measured. TMB was 4.3 +/- 1 min for pancuronium, 3.5 +/- 0.8 min for atracurium, and 3.3 +/- 0.98 min for vecuronium. The differences between pancuronium and the other drugs were statistically significant, but they were not so between the latter two. TCE was 67.9 +/- 13.5 min for pancuronium, significantly longer than with vecuronium and atracurium (28.2 +/- 5.7 and 31.5 +/- 4.7, respectively). TDT was 126.2 +/- 19.9 min for pancuronium, 61.2 +/- 11.5 min for atracurium and 55.5 +/- 16.7 for vecuronium. The mean duration of the repeated dose was 52.7 +/- 8.4 min for pancuronium, 19.9 +/- 5 min for vecuronium and 10.9 +/- 5 min for atracurium. RI, which was similar for atracurium and vecuronium (12.7 +/- 1.7 min and 12.8 +/- 3.3 min), was longer for pancuronium (27.7 +/- 4.3 min).

[The use of antihomotoxic therapy in dentistry]. / Primenenie antigomotoksicheskoi terapii v stomatologii.

Efficacy of traumel C is assessed in patients with various maxillofacial inflammations. Sixty-nine patients with diseases of the buccal mucosa (aphthous stomatitis, herpes labialis, and perlèches), periodontal tissues, and painful syndrome after dental canal filling were treated. Applications of the drug were administered to patients with diseases of the buccal mucosa and slight or medium-severe periodontitis. Patients with grave periodontitis and pain after dental canal filling were injected with traumel solution. Positive shifts were attained in all cases. The duration of treatment depended on the process severity. The results recommend traumel C as an ointment for local applications and an injection solution for combined therapy of diseases of the buccal mucosa and periodontitis. The treatment schemes are convenient for outpatient treatment; there are no contraindications precluding the drug use. No side effects were observed.

Evaluating homeopathic drugs within a biomedical framework.

The concept of hormesis can provide an evaluation framework for the assessment of homeopathic treatment preparations following a post-conditioning hormesis protocol based on the research of van Wijk and colleagues. This proposal would require that doses of administered drug conform to analytical chemistry requirements for quantification. This developmental framework can provide a scientific 'point of contact' between the homeopathic and biomedical communities, which has long been lacking.